HRP20040151A2 - Alkyne-aryl phosphodiesterase-4 inhibitors - Google Patents

Abstract

The compounds represented by formula (I): or pharmaceutically acceptable salts thereof, are phosphodiesterase-4 inhibitors, useful in the treatment of asthma and inflammation.

Description

Field of invention

The present invention relates to compounds which are alkyne-aryl substituted 1,8-naphthyridin-4(1H)-ones. In particular, this invention relates to phenyl substituted 1,8-naphthyridin-4(1H)-one, which are phosphodiesterase-4 inhibitors, where the phenyl group is at the 1-position and contains a 2-alkyne substituent group, further optionally substituted.

Background of the invention

Hormones are compounds that have a diverse effect on cellular activity. In many ways, hormones act as messengers that elicit specific cellular responses and activities. Many hormone-induced actions, however, are not caused by the action of hormones alone. Instead, the hormone first binds to a receptor, causing the release of a medicinal compound, which affects cellular activity. In this scenario, the hormone is known as the first messenger, while the other compound is called the second messenger. Cyclic adenosine monophosphate (adenosine 3',5'-cyclic monophosphate, "cAMP" or "cyclic AMP") is known as a second messenger for hormones, including epinephrine, glucagon, calcitonin, corticotrophin, lipotropin, luteinizing hormone, norepinephrine, parathyroid hormone, thyroid-stimulating hormone, and vasopressin. Therefore, cAMP mediates cellular responses to hormones. Cyclic AMP also mediates cellular responses to various neurotransmitters.

Phosphodiesterases ("PDEs") are a family of enzymes that metabolize 3', 5' cyclic nucleotides to 5' nucleoside monophosphate, thereby completing cAMP's second messenger activity. A particular phosphodiesterase, phosphodiesterase-4 ('TDE4'), also known as "PDE-IV"), which is a cAMP-specific, high-affinity type IV PDE, is attracting interest as potential targets for the development of new anti-asthmatic and anti- inflammatory compounds. PDE4 exists as at least four isoenzymes, each encoded by a different gene. Each of the four known PDE4 gene products is believed to play a different role in allergic and/or inflammatory responses.

Therefore, it is believed that inhibition of PDE4, especially specific PDE4 isoforms that produce adverse responses, may have a beneficial effect on allergy and inflammatory symptoms. It would be desirable to provide new compounds and compositions that inhibit PDE4 activity.

A major problem in the use of PDE4 inhibitors is the side effect of nausea and vomiting that has been observed for several candidate compounds, as described in C. Burnouf et al., ("Burnouf'), Ann. Rep. In Med. Chem,, 33:91-109 (1998). B. Hughes et al., Br J. Pharmacol, 118:1183-1191(1996); MJ. Perry et al., Cellular Biochem. Biophys., 29:113-132(1998); S. B. Christensen et al., J. Med Chem., 41:821-835(1998); and Burnouf describe wide variations in the severity of adverse side effects exhibited by various compounds. As described in MD. Houslav et al., Adv. In Pharmacol., 44 :225-342(1998) and D. Spina et al., Adv. In Pharmacol., 44:33-89(1998), there is great interest and research into therapeutic PDE4 inhibitors.

International Patent Application WO9422852 describes quinolines as PDE4 inhibitors. International Patent Application WO9907704 describes l-aryl-1,8-naphthylidin-4-one derivatives as PDE4 inhibitors.

A.H. Cook, et al., J.Chem. Soc., 413-417 (1943) describes gamma-pyridylquinoline. Other quinoline compounds are described in Kei Manabe et al., J.Org. Chem., 58(2):6692-6700(1993); Kei Manabe et al., J.Am. Chem. Soc., 115(12):5324-5325(1993); and Kei Manabe et al., J. Am. Chem. Soc., 114(17):6940-6941(1992).

Compounds containing ring systems have been described by various researchers as effective for a variety of therapies and uses. For example, International Patent Application No. WO 98/25883 describes ketobenzamide as inhibitors, European Patent Application No. EP 811610 and U.S. Pat. Patent No. 5,679,712, 5,693,672 and 5,747,541 describe substituted benzoylguanidine sodium channel blockers, U.S. Pat. Patent No. 5,736,297 describes ring systems useful as photosensitive compositions.

LOUSE. Patent No. 5,491,147, 5,608,070, 5,622,977, 5,739,144, 5,776,958, 5,780,477, 5,786,354, 5,798,373, 5,849,770, 5,859,034, 5,866,593, 5,891,896, i Međunarodna Patentna Prijava WO 95/35283 opisuju PDE4 inhibitore koji su tri-supstituirani aril ili heteroaril fenil derivati. LOUSE. Patent No. 5,580,888 discloses PDE4 inhibitors containing derivatives. LOUSE. Patent No. 5,550,137 describes PDE4 inhibitors which are phenylaminocarbonyl derivatives. LOUSE. Patent No. 5,340,827 describes PDE4 inhibitors which are phenylcarboxamide compounds, U.S. Pat. Patent No. 5,780,478 describes PDE4 inhibitors, which are tetra-substituted phenyl derivatives. International Patent Application WO 96/00215 describes substituted oxime derivatives useful as PDE4 inhibitors. LOUSE. Patent No. 5,633,257 describes PDE4 inhibitors that are cycloalkyl and alkenyl)phenyl-alkenyl (aryl and heteroaryl) compounds.

However, there remains a need for new compounds and preparations that therapeutically inhibit PDE4 with minimal side effects.

Summary of the invention

The present invention relates to alkyne-aryl substituted 1,8-naphthyridin-4(1H)-one represented by formula (I):

[image]

or its pharmaceutically acceptable salts, which are phosphodiesterase-4 inhibitors.

The present invention also provides pharmaceutical compositions comprising an effective amount of a novel alkyne-aryl substituted 1,8-naphthyridin-4(1H)-one and a pharmaceutically acceptable carrier. The present invention further provides a method of treating mammals, for example, i) pulmonary disorders such as asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome, pediatric respiratory distress syndrome, cough, chronic obstructive pulmonary disease in animals, respiratory distress syndrome in adults, and respiratory distress syndrome in children, ii) gastrointestinal disorders such as ulcerative colitis, Crohn's disease, and hypersecretion of gastric acid, iii) infectious diseases such as bacterial, fungal or viral sepsis or septic shock, endotoxic shock (and related conditions such as laminitis and spasms in horses), and septic shock, iv) neurological disorders such as spinal cord trauma, head injuries, neurogenic inflammation, pain, and brain reperfusion injuries, v) inflammatory disorders such as psoriatic arthritis, rheumatic arthritis, ankylosing spondylitis, osteoarthritis, inflammation and cytokine-mediated ana chronic tissue degeneration, vi) allergic disorders such as allergic rhinitis, allergic conjunctivitis, and eosinophilic granuloma, vii) psychiatric disorders such as depression, memory impairment, and monopolar depression, viii) neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, acute and chronic multiple sclerosis, ix) dermatological disorders such as psoriasis and other benign or malignant proliferative skin diseases, atopic dermatitis, and urticaria, x) oncological diseases such as cancer, tumor growth and cancerous invasion of normal tissue , xi) metabolic disorders such as diabetes insipidus, xii) bone disorders such as osteoporosis, xiii) cardiovascular disorders such as arterial restenosis, arteriosclerosis, myocardial reperfusion injury, and xiv) other disorders, such as chronic glomerulonephritis, vernal conjunctivitis , rejection of transplants and implants, and cachexia - diseases that are subject to pain by inhibiting the PDE4 isoenzyme and the resulting elevated cAMP levels - by administering an effective amount of a new alkyne-aryl substituted 1,8-naphthyridin-4(1H)-one or precursor compound, which forms in vivo a new alkyne-aryl substituted 1,8-naphthyridine -4(1H)-one, which is a phosphodiesterase-4 inhibitor.

Detailed description of the invention

The compound of this invention is represented by formula (I):

[image]

or its pharmaceutically acceptable salts, where

R is H, -C1-6alkyl or -C3-6cycloalkyl;

R 1 is H, or -C 1-6 alkyl, -C 3-6 cycloalkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 3-6 alkynyl, -C(O)-C 1-6 alkyl, -C(O)-aryl, -( C0-6alkyl)-SOn-C1-6alkyl), -(C0-6alkyl)-SOn-(aryl), phenyl, heteroaryl, or heterocycloC3-7alkyl group, where any of the groups is optionally substituted with 1-3 independent -C1 -6alkyl, -C1-6alkyl, OH, -N(C0-6alkyl)(C0-6alkyl), -(C0-6alkyl)-SOn-(C1-6alkyl), nitro, CN, =N-O-C1-6alkyl, - O-N=C1-6 alkyl, or halogen of the substituent;

R 2 is absent, H, halogen, -C 1-6 alkyl, -C 3-6 cycloalkyl, -C 1-6 alkyl(C 3-6 cycloalkyl)(C 3-6 cycloalkyl), -C 1-6 alkoxy, phenyl, heteroaryl, heterocycloC 3-7 alkyl, nitro, CN, =N-O-C1-6alkyl, -O-N=C1-6alkyl, -N(C0-6alkyl)(C0-6alkyl), -NHSOn-(C1-6alkyl), -NHC(O)-C1-6alkyl, -NHC(O )-aryl, -C(O)-C1-6alkyl, -C(O)-O-C1-6alkyl, -C1-6alkyl(-N-OH), -C(N=NOH)C1-6alkyl, -C0 -6alkyl(oxy)C1-6alkyl-phenyl, -SOnNH(C0-6alkyl), or -(C0-6alkyl)-SOn-(C1-6alkyl), where phenyl, heteroaryl or heterocycloC3-7alkyl is optionally substituted with halogen, - C 1-6 alkyl, -C 1-6 alkoxy, hydroxy, -N(C 0-6 alkyl)(C 0-6 alkyl), or -C(O)-O-C 1-6 alkyl, and each alkyl is optionally substituted with 1-6 independent halogen or -OH of the substituent;

n is 0, 1, or 2;

R3 is absent, H, OH, -N(C0-6alkyl)(C0-6alkyl), halogen or C1-6alkyl, where each alkyl is optionally substituted with 1-6 independent halogens, OH, or -N(C0-6alkyl) (C0-6alkyl) substituent;

R 4 , R 5 , R 6 , and R 7 are each independently H, halogen, -C 1-6 alkyl, -C 1-6 alkoxy, -SOn-(C 1-6 alkyl), nitro, CN, or -N(C 0-6 alkyl)(C 0-6 alkyl ), and every one is alki! optionally substituted with 1-6 independent halogen or -OH substituents; and

R 8 is phenyl, pyridyl, pyrimidyl, indolyl, quinolinyl, thienyl, pyridonyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, or imidazolyl; or their oxides when R 8 is heteroaryl; or H, -C1-6alkyl, or -C3-6cycloalkyl, and each alkyl is optionally substituted with 1-6 independent halogens, -N(C0-6alkyl)(C0-6alkyl), -N(C3-7cycloalkyl)(C0- 6alkyl), -N(C3-7cycloalkyl)(C3-7cycloalkyl), N-heterocycloC4-7alkyl, -SOn-(C1-6alkyl), -SOn-(aryl), or -OH substituents.

In one aspect, a compound of the present invention is represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein

R is H, -C1-6alkyl or -C3-6cycloalkyl;

R 1 is H, or -C 1-6 alkyl, -C 3-6 cycloalkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 3-6 alkynyl,-C(O)-C 1-6 alkyl,-C(O)-aryl,-( C0-6alkyl)-SOn-(C1-6alkyl), (C0-6alkyl)-SOn-(aryl), phenyl, heteroaryl, or heterocycloC3-7alkyl group, wherein any of the groups is optionally substituted with 1-3 independent -C1 -6alkyl, -C1-6alkyl, OH,-N(C0-6alkyl)(C0-6alkyl), -(C0-6alkyl)-SOn-(C1-6alkyl), nitro, CN, =N-O-C1-6alkyl, - O-N=C1-6 alkyl, or halogen of the substituent;

R2 is absent;

n is 0, 1, or 2;

R3 is absent;

R 4 , R 5 , R 6 , and R 7 are each independently H, halogen, -C 1-6 alkyl, -C 1-6 alkoxy, -SOn-(C 1-6 alkyl), nitro, CN, or -N(C 0-6 alkyl)(C 0-6 alkyl ), and each alkyl is optionally substituted with 1-6 independent halogen or -OH substituents; and

R8 is H.

In another aspect, a compound of the present invention is represented by formula (1) or a pharmaceutically acceptable salt thereof, where

R is H, -C1-6alkyl or -C3-6cycloalkyl;

R 1 is H, or -C 1-6 alkyl, -C 3-6 cycloalkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 3-6 alkynyl, -C(O)-C 1-6 alkyl, -C(O)-aryl, -( C0-6alkyl)-SOn-(C1-6alkyl), -(C0-6alkyl)-SOn-(aryl), phenyl, heteroaryl, or heterocycloC3-7alkyl group, where any of the groups is optionally substituted with 1-3 independent - C1-6alkyl, -C1-6alkyl, OH, -N(C0-6alkyl)(C0-6alkyl), -(C0-6alkyl)-SOn-(C1-6alkyl), nitro, CN, =N-O-C1-6alkyl, -O-N=C1-6alkyl, or halogen of the substituent;

R2 is absent, H, halogen, -C1-6alkyl, -C3-6cycloalkyl, -C1-6alkyl(C3-6cycloalkyl)(C3-6cyldoalkyl), -C1-6alkoxy, phenyl, heteroaryl, heterocycloC3-7alkyl, nitro, CN, =N-O-C1-6alkyl, -O-N=C1-6alkyl, -N(C0-6alkyl)(C0-6alkyl), -NHSOn-(C1-6alkyl), -NHC(O)-C1-6alkyl, -NHC(O )-aryl, -C(O)-C1-6alkyl, -C(O)-O-C1-6alkyl, -C1-6alkyl(=N-OH), -C(N=NOH)C1-6alkyl, -C0 -6alkyl(oxy)C1-6alkyl-phenyl, -SOnNH(C0-6alkyl), or -(C0-6alkyl)-SOn-(C1-6alkyl), where phenyl, heteroaryl or heterocycloC3-7alkyl is optionally substituted with halogen, -C 1-6 alkyl, -C 1-6 alkoxy, hydroxy, -N(C 0-6 alkyl)(C 0-6 alkyl), or -C(O)-O-C 1-6 alkyl, and each alkyl is optionally substituted with 1-6 independent halogens or -OH of the substituent;

n is 0, 1, or 2;

R3 is absent, H, OH, -N(C0-6alkyl)(C0-6alkyl), halogen or C1-6alkyl, where each alkyl is optionally substituted with 1-6 independent halogen, OH, or -N(C0-6alkyl) (C0-6alkyl) substituent;

R 4 , R 5 , R 6 , and R 7 are each independently H, halogen, -C 0-6 alkyl, -C 0-6 alkoxy, -SOn-(C 1-6 alkyl), nitro, CN, or -N(C 0-6 alkyl)(C 0-6 alkyl ), and each alkyl is optionally substituted with 1-6 independent halogen or -OH substituents; and

R 8 is phenyl, pyridyl, pyrimidyl, indolyl, quinolinyl, thicnyl, pyridonyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, or imidazolyl; or its oxide when R 8 is heteroaryl.

In an implementation of another aspect, a compound of the present invention is represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein

R is H, -C1-6alkyl or -C3-6cycloalkyl;

R 1 is H, or -C 1-6 alkyl, -C 3-6 cycloalkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 3-6 alkynyl, -C(O)-C 1-6 alkyl, -C(O)-aryl, -( C0-6alkyl)-SOn-(C1-6alkyl), -(C0-6alkyl)-SOn-(aryl), phenyl, heteroaryl, or heterocycloC3-7alkyl group, where any of the groups is optionally substituted with 1-3 independent - C1-6alkyl, -C1-6alkyl, OH, -N(C0-6alkyl)(C0-6alkyl), -(C0-6alkyl)-SOn-(C1-6alkyl), nitro, CN, =N-O-C1-6alkyl, -O-N=C1-6alkyl, or halogen of the substituent;

R 2 is absent, H, halogen, -C 1-6 alkyl, -C 3-6 cycloalkyl, -C 1-6 alkyl(C 3-6 cycloalkyl)(C 3-6 cycloalkyl), -C 1-6 alkoxy, phenyl, heteroaryl, heterocycloC 3-7 alkyl, nitro, CN, =N-O-C1-6alkyl, -O-N=C1-6alkyl, -N(C0-6alkyl)(C0-6alkyl), -NHSOn-(C1-6alkyl), -NHC(O)-C1-6alkyl, -NHC(O )-aryl, -C(O)-C1-6alkyl, -C(O)-O-C1-6alkyl, -C1-6alkyl(=N-OH), -C(N=NOH)C1-6alkyl, -C0 -6alkyl(oxy)C1-6alkyl-phenyl, -SOnNH(C0-6alkyl), or -(C0-6alkyl)-SOn-(C1-6alkyl), where phenyl, heteroaryl or heterocycloC3-7alkyl is optionally substituted with halogen, -C 1-6 alkyl, -C 1-6 alkoxy, hydroxy, -N(C 0-6 alkyl)(C 0-6 alkyl), or -C(O)-O-C 1-6 alkyl, and each alkyl is optionally substituted with 1-6 independent halogen or -OH of the substituent;

n is 0, 1, or 2;

R3 is absent, H, OH, -N(C0-6alkyl)(C0-6alkyl), halogen or C1-6alkyl, where each alkyl is optionally substituted with 1-6 independent halogen, OH, or -N(C0-6alkyl) (C0-6alkyl) substituent;

R 4 , R 5 , R 6 , and R 7 are each independently H, halogen, -C 1-6 alkyl, -C 1-6 alkoxy, -SOn(C 1-6 alkyl), nitro, CN, or -N(C 0-6 alkyl)(C 0-6 alkyl) , and each alkyl is optionally substituted with 1-6 independent halogen or -OH substituents; and

R 8 is phenyl.

In another implementation of another aspect, a compound of the present invention is represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein

R is H, -C1-6alkyl or -C3-6cycloalkyl;

R 1 is H, or -C 1-6 alkyl, -C 3-6 cycloalkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 3-6 alkynyl, -C(O)-C 1-6 alkyl, -C(O)-aryl, -( C0-6alkyl)-SOn-(C1-6alkyl), -(C0-6galkyl)-SOn-(aryl), phenyl, heteroaryl, or heterocycloC3-7alkyl group, where any of the groups is optionally substituted with 1-3 independent - C1-6alkyl, -C1-6alkyl, OH, -N(C0-6alkyl)(C0-6alkyl), -(C0-6alkyl)-SOn-H(C1-6alkyl), nitro, CN, =N-O-C1-6alkyl , -O-N=C1-6alkyl, or halogen of the substituent;

R 2 is absent, H, halogen, -C 1-6 alkyl, -C 3-6 cycloalkyl, -C 1-6 alkyl(C 3-6 cycloalkyl)(C 3-6 cycloalkyl), -C 0-6 alkoxy, phenyl, heteroaryl, heterocycloC 3-6 alkyl, nitro, CN, =N-O-C1-6alkyl, -O-N=C1-6alkyl, -N(C0-6alkyl)(C0-6alkyl), -NHSOn-(C1-6alkyl), -NHC(O)-(C1-6alkyl, -NHC( O)-aryl, -(C(O)C1-6alkyl, -C(O)-O-C1-6alkyl, -C1-6alkyl(=N-OH), -(C(N=NOH)C1-6alkyl, -C0-6alkyl(oxy)-C1-6alkyl-phenyl, -SOnNH(C0-6alkyl), or -(C0-6alkyl)-SOn-(C1-6alkyl), where phenyl, heteroaryl or heterocycloC3-7alkyl is optionally substituted with halogen, -C 1-6 alkyl, -C 1-6 alkoxy, hydroxy, -N(C 0-6 alkyl)(C 0-6 alkyl), or -C(O)-O-C 1-6 alkyl, and each alkyl is optionally substituted with 1- 6 independent halogen or -OH substituents;

n is 0, 1, or 2;

R3 is absent, H, OH, -N(C0-6alkyl)(C0-6alkyl), halogen or C1-6alkyl, where each alkyl is optionally substituted with 1-6 independent halogens, OH, or -N(C0-6alkyl) (C0-6alkyl) substituent;

R 4 , R 5 , R 6 , and R 7 are each independently H, halogen, -C 1-6 alkyl, -C 1-6 alkoxy, -SOn-(C 1-6 alkyl), nitro, CN, or -N(C 0-6 alkyl)(C 0-6 alkyl ), and each alkyl is optionally substituted with 1-6 independent halogen or -OH substituents; and

R8 is pyridyl, or its oxide.

In yet another implementation of the second aspect, a compound of the present invention is represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein

R is H, -C1-6alkyl or -C3-6cycloalkyl;

R 1 is H, or -C 1-6 alkyl, -C 3-6 cycloalkyl; -C1-6Alkoxy, -C2-6alkenyl, -C3-6alkynyl, -C(O)-C1-6alkyl, -C(O)-aryl, -(C0-6alkyl)-SOn-(C1-6alkyl), -( C0-6alkyl)-SOn-(aryl), phenyl, heteroaryl, or heterocycloC3-7alkyl group, wherein any of the groups is optionally substituted with 1-3 independent -C1-6alkyl, -C1-6alkoxy, OH, -N(C0 -6alkyl)(C0-6alkyl), -(C0-6alkyl)-SOn-(C1-6alkyl), nitro, CN, =N-O-C1-6alkyl, -O-N=C1-6alkyl, or a halogen substituent;

R 2 is absent, H, halogen, -C 1-6 alkyl, -C 3-6 cycloalkyl, -C 1-6 alkyl(C 3-6 cycloalkyl)(C 3-6 cycloalkyl), -C 1-6 alkoxy, phenyl, heteroaryl, heterocycloC 3-7 alkyl, nitro, CN, =N-O-C1-6alkyl, -O-N=C1-6alkyl, -N(C0-6alkyl)(C0-6alkyl), -NHSOn-(C1-6alkyl), -NHC(O)-C1-6alkyl, -NHC(O )-aryl, -C(O)-C1-6alkyl, -C(O)-O-C1-6alkyl, -C1-6alkyl(-N-OH), -C(N=NOH)C1-6alkyl, -C0 -6alkyl(oxy)C1-6alkyl-phenyl, -SOnNH(C0-6alkyl), or -(C0-6alkyl)-SOn-(C1-6alkyl), where phenyl, heteroaryl or heterocycloC3-7alkyl is optionally substituted with halogen, -C 1-6 alkyl, -C 1-6 alkoxy, hydroxy, -N(C 0-6 alkyl)(C 0-6 alkyl)} or -C(O)-O-C 1-6 alkyl, and each alkyl is optionally substituted with 1-6 independent halogens or -OH of the substituent;

n is 0, 1, or 2;

R3 is absent, H, OH, -N(C0-6alkyl)(C0-6alkyl), halogen or C1-6alkyl, where each alkyl is optionally substituted with 1-6 independent halogens, OH, or -N(C0-6alkyl) (C0-6alkyl) substituent;

R4, R5, R6, and R7 are each independently H, halogen, -C1-6alkyl, -C1-galkoxy, -SOn-(C1-ealkyl), nitro, CN, or -N(C0-6alkyl)(C0-6alkyl ), and each alkyl is optionally substituted with 1-6 independent halogens or -OH substituents; and

R8 is quinolinyl, or its oxide.

In yet another implementation of the second aspect, a compound of the present invention is represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein

R is H, -C1-6alkyl or -C3-6cycloalkyl;

R 1 is H, or -C 1-6 alkyl, -C 3-6 cycloalkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 3-6 alkynyl, -C(O)-C 1-6 alkyl, -C(O)-aryl, -( C0-6alkyl)-SOn-(C1-6alkyl), -(C0-6alkyl)-SOn-(aryl), phenyl, heteroaryl, or heterocycloC3-7alkyl group, where any of the groups is optionally substituted with 1-3 independent - C1-6alkyl, -C1-6alkyl, OH, -N(C0-6alkyl)(C0-6alkyl), -(C0-6alkyl)-SOn-(C1-6alkyl), nitro, CN, =N-O-C1-6alkyl, -O-N=C1-6alkyl, or halogen of the substituent;

R2 is absent, H, halogen, -C1-6alkyl, -C3-6cycloalkyl,

-C1-6alkyl(C3-6cycloalkyl)(C3-6cycloalkyl), -C0-6Alkoxy, phenyl, heteroaryl, heterocycloC3-7alkyl, nitro, CN, =N-O-C1-6alkyl, O-N=C1-6alkyl, -N(C0- 6alkyl)(C0-6alkyl), -NHSOn-(C1-6alkyl), -NHC(O)-C1-6alkyl, -NHC(O)-aryl, -C(O)-C1-6alkyl, -C(O) -O-C1-6alkyl, -C1-6alkyl(=N-OH), -C(N=NOH)C1-6alkyl, -C0-6alkyl(oxy)C1-6alkyl-phenyl, -SOnNH(C0-6alkyl), or -(C0-6alkyl)-SOn-(C1-6alkyl)s where the phenyl, heteroaryl or heterocycloC3-7alkyl is optionally substituted with halogen, -C1-6alkyl, -C1-6alkoxy, hydroxy, -N(C0-6alkyl)( C0-6alkyl), or -C(O)-O-C1-6alkyl, and each alkyl is optionally substituted with 1 -6 independent halogen and 1 -OH substituents;

n is 0, 1, or 2;

R3 is absent, H, OH, -N(C0-6alkyl)(C0-6alkyl), halogen or C1-6alkyl, where each alkyl is optionally substituted with 1-6 independent halogen, OH, or -N(C0-6alkyl) (C0-6alkyl) substituent;

R 4 , R 5 , R 6 , and R 7 are each independently H, halogen, -C 1-6 alkyl, -C 1-6 alkoxy, -SOn-(C 1-6 alkyl), nitro, CN, or -N(C 0-6 alkyl)(C 0-6 alkyl ), and each alkyl is optionally substituted with 1-6 independent halogen or -OH substituents; and

R8 is thienyl, or its oxide.

In another embodiment of another aspect, a compound of the present invention is represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein

R is H, -C1-6alkyl or -C3-6cycloalkyl;

R 1 is H, or -C 1-6 alkyl, -C 3-6 cycloalkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 3-6 alkynyl, -C(O)-C 1-6 alkyl, -C(O)-aryl, -( C0-6alkyl)-SOn-(C1-6alkyl), -(C0-6alkyl)-SOn-(aryl), phenyl, heteroaryl, or heterocycloC3-7alkyl group, where any of the groups is optionally substituted with 1-3 independent - C1-6alkyl, -C1-6alkyl, OH, -N(C0-6alkyl)(C0-6alkyl), -(C0-6alkyl)-SOn-(C1-6alkyl), nitro, CN, =N-O-C1-6alkyl, -O-N=C1-6alkyl, or halogen of the substituent;

R 2 is absent, H, halogen, -C 1-6 alkyl, -C 3-6 cycloalkyl, -C 1-6 alkyl(C 3-6 cycloalkyl)(C 3-6 cycloalkyl), -C 1-6 alkoxy, phenyl, heteroaryl, heterocycloC 3-7 alkyl, nitro, CN, =N-O-C1-6alkyl, -O-N=C1-6alkyl, -N(C0-6alkyl)(C0-6alkyl), -NHSOn-(C1-6alkyl), -NHC(O)-C1-6alkyl, -NHC(O )-aryl, -C(O)-C1-6alkyl, -C(O)-C1-6alkyl, -C1-6alkyl(=N-OH), -C(N=NOH)C1-6alkyl, -C0-6alkyl (oxy)C1-6alkyl-phenyl, -SOnNH(C0-6alkyl), or -(C0-6alkyl)-SOn-(C1-6alkyl), where phenyl, heteroaryl or heterocycloC3-7alkyl is optionally substituted with halogen, -C1 -6alkyl, -C1-6 alkoxy, hydroxy, -N(C0-6alkyl)(C0-6alkyl), or -C(O)-O-C1-6alkyl, and each alkyl is optionally substituted with 1-6 independent halogen or - OH of the substituent;

n is 0, 1, or 2;

R3 is absent, H, OH, -N(C0-6alkyl)(C0-6alkyl), halogen or C1-6alkyl, where each alkyl is optionally substituted with 1-6 independent halogens, OH, or -N(C0-6alkyl) (C0-6alkyl) substituent;

R4, R5, R6, and R7 are each independently H, halogen, -C0-6alkyl, -C1-6alkyl, -SOn-(C1-6alkyl), nitro, CN, or -N(C0-6alkyl)(C0-6alkyl ), and each alkyl is optionally substituted with 1-6 independent halogen or -OH substituents; and

R8 is thiazolyl, or its oxide.

In a third aspect, a compound of the present invention is represented by formula (1) or a pharmaceutically acceptable salt thereof, wherein

R is H, -C1-6alkyl or -C3-6cycloalkyl;

R 1 is H, or -C 1-6 alkyl, -C 3-6 cycloalkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 3-6 alkynyl, -C(O)-C 1-6 alkyl, -C(O)-aryl, -( C0-6alkyl)-SOn-(C1-6alkyl), -(C0-6-alkyl)-SOn-(aryl), phenyl, heteroaryl, or heterocycloC3-7alkyl group, where any of the groups is optionally substituted with 1-3 independent –C1-6alkyl, -C1-6Alkoxy, OH, -N(C0-6alkyl)(C0-6alkyl), -(C0-6alkyl)-SOn-(C1-6aIkii), nitro, CN, =N-O-C1- 6alkyl, -O-N=C1-6alkyl, or halogen of the substituent;

R2 is absent, H, halogen, -C0-6alkyl, -C3-6cycloalkyl,

-C1-6alkyl(C3-6cycloalkyl)(C3-6cycloalkyl), -C1-6Alkoxy, phenyl, heteroaryl, heterocycloC3-7alkyl, nitro, CN, =N-O-C1-6alkyl, -O-N=C1-6alkyl, -N(C0 -6alkyl)(C0-6alkyl), -NHSOn-(C1-6alkyl), -NHC(O)-C1-6alkyl, -NHC(O)-aryl, -C(O)-C1-6alkyl, -C(O )-O-C1-6alkyl, -C1-6alkyl(=N-OH), -C(N=NOH)C1-6alkyl, -C0-6alkyl(oxy)C1-6alkyl-phenyl, -SOnNH(C0-6alkyl) , or -(C0-6alkyl)-SOn-(C1-6alkyl), where phenyl, heteroaryl, or heterocycloC3-7alkyl is optionally substituted with halogen, -C1-6alkyl, -C1-6alkoxy, hydroxy, -N(C0-6alkyl )(C0-6alkyl), or -C(O)-O-C1-6alkyl, and each alkyl is optionally substituted with 1-6 independent halogen or -OH substituents;

n is 0, 1, or 2;

R3 is absent, H, OH, -N(C0-6alkyl)(C0-6alkyl), halogen or C1-6alkyl, where each alkyl is optionally substituted with 1-6 independent halogens, OH, or -N(C0-6alkyl) (C0-6alkyl) substituent;

R 4 , R 5 , R 6 , and R 7 are each independently H, halogen, -C 1-6 alkyl, -C 1-6 alkoxy, -SOn-(C 1-6 alkyl), nitro, CN, or -N(C 0-6 alkyl)(C 0-6 alkyl ), and each alkyl is optionally substituted with 1-6 independent halogen or -OH substituents; and

R8 is -C3-6cycloalkyl, optionally substituted with 1-6 independent halogen, -N(C0-6alkyl)(C0-6alkyl), -N(C3-7cycloalkyl)(C0-6alkyl), -N(C3-7cycloalkyl)( C3-7cycloalkyl), N-heterocycloC3-7alkyl, -SOn-(C1-6alkyl), -SOn-(aryl), or -OH substituent.

In a fourth aspect, a compound of the present invention is represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein

R is H, -C1-6alkyl or -C3-6cycloalkyl;

R 1 is H, or -C 1-6 alkyl, -C 3-6 cycloalkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 3-6 alkynyl, -C(O)-C 1-6 alkyl, -C(O)-aryl, -( C0-6alkyl)-SOn-(C1-6alkyl), -(C0-6alkyl)-SOn-(aryl), phenyl, heteroaryl, or heterocycloC3-7alkyl group, where any of the groups is optionally substituted with 1-3 independent - C1-6alkyl, -C1-6alkyl, OH, -N(C0-6alkyl)(C0-6alkyl), -(C0-6alkyl)-SOn-(C1-6alkyl), nitro, CN, =N-O-C1-6alkyl, -O-N=C1-6alkyl, or halogen of the substituent;

R2 is absent, H, halogen, -C1-6alkyl, -C3-6cycloalkyl,

-C1-6alkyl(C3-6cycloalkyl)(C3-6cycloalkyl), -C1-6Alkoxy, phenyl, heteroaryl, heterocycloC3-7alkyl, nitro, CN, =N-O-C1-6alkyl, -O-N=C1-6alkyl, -N(C0 -6alkyl)(C0-6alkyl), -NHSOn-(C1-6alkyl), -NHC(O)-C1-6alkyl, -NHC(O)-aryl, -C(O)-C1-6alkyl, -C(O )-O-C1-6alkyl, -C1-6alkyl(=N-OH), -C(N=NOH)C1-6alkyl, -C0-6alkyl(oxy)C1-6alkyl-phenyl, -SOnNH(C0-6alkyl) . )(C0-6alkyl), or -C(O)-O-C1-6alkyl, and each alkyl is optionally substituted with 1-6 independent halogen or -OH substituents;

n is 0, 1, or 2;

R3 is absent, H, OH, -N(C0-6alkyl)(C0-6alkyl), halogen or C1-6alkyl, where each alkyl is optionally substituted with 1-6 independent halogens, OH, or -N(C0-6alkyl) (C0-6alkyl) substituent;

R 4 , R 5 , R 6 , and R 7 are each independently H, halogen, -C 1-6 alkyl, -C 1-6 alkoxy, -SOn-(C 1-6 alkyl), nitro, CN, or -N(C 0-6 alkyl)(C 0-6 alkyl ), and each alkyl is optionally substituted with 1-6 independent halogen or -OH substituents; and

R8 is -C1-6alkyl, optionally substituted with 1-6 independent halogens, -N(C0-6alkyl)(C0-6alkyl, -N(C3-7cycloalkyl)(C0-6alkyl), -N(C3-7cycloalkyl)(C3 -7cycloalkyl), N-heterocycloC4-7alkyl, -SOn-(C1-6alkyl), -SOn-(aryl), or -OH substituent.

As used herein, "alkyl" as well as other groups prefixed with "alk" such as, for example, alkoxy, alkanoyl, alkenyl, alkynyl and the like, refer to carbon chains which may be straight or branched or combinations thereof. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl and the like. "Alkenyl", "alkynyl" and other similar terms include carbon chains containing at least one unsaturated C-C bond.

The term "cycloalkyl" denotes carbocyclics, which do not contain heteroatoms, including mono-, bi- and tricyclic saturated carbocycles, as well as fused ring systems. Such fused ring systems may contain one ring, which is partially or fully unsaturated, such as benzene rings, to obtain a system of condensed rings, such as well-condensed carbocycles. Cycloalkyl contains such fused ring systems as spiro fused rings. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decahydronaphthalenyl, adamantanyl, indanyl, indenyl, fluorenyl, 1,2,3,4-tetrahydronaphthalenyl, and the like. Similarly, "cycloalkenyl" refers to carbocyclics containing no heteroatoms and at least one non-aromatic C-C double bond, including mono-, bi- and tricyclic partially saturated carbocyclics, as well as benzofused cycloalkenes. Examples of cycloalkenyl include cyclohexenyl, indenyl, and the like.

The term "cycloalkyloxy" unless otherwise indicated contains a cycloalkyl group attached to an oxy bonding atom.

The term "alkoxy", unless expressly indicated otherwise, includes an alkyl group attached to an oxy bonding atom.

The term "aryl", unless otherwise indicated, includes multiple ring systems as well as single ring systems, such as, for example, phenyl or naphthyl.

The term "aryloxy", unless expressly indicated otherwise, includes multiple ring systems as well as single ring systems, such as, for example, phenyl or naphthyl, linked through an oxy bonding atom to the bonding site.

The term "C 0 -C 6 alkyl" includes alkyls containing 6, 5, 4, 3, 2, 1, or no carbon atoms. Alkyl without carbon atoms is a hydrogen atom substituent when the alkyl is the terminal moiety. Alkyl without carbon atoms is directly attached, when the alkyl is a bridging moiety.

The term "hetero", unless otherwise indicated, contains one or more O, S, or N atoms. For example, heterocycloalkyl and heteroaryl contain ring systems containing one or more O, S, or N ring atoms, including mixtures of such atoms. Heteroatoms replace the carbon atoms in the ring. Thus, for example, heterocycloCsalkyl is a five-membered ring containing from 5 to no carbon atoms.

Examples of heteroaryl include, for example, pyridinyl, quinolinyl, isoquinolinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinoxalinyl, furyl, benzofuryl, dibenzofuryl, thienyl, benzothienyl, pyrrolyl, indolyl, pyrazolyl, indazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, benzimidazoHl. , oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl.

The term "heteroaryloxy", unless otherwise indicated, describes a heteroaryl group attached through an oxy bonding atom to the bonding site.

Examples of heteroaryl(C1-6)alkyl include, for example, furylmethyl, furylethyl, thienylmethyl, thienylethyl, pyrazolylmethyl, oxazolylmethyl, oxazolylethyl, isoxazolylmethyl, thiazolylmethyl, thiazolylethyl, imidazolylmethyl, imidazolylethyl, benzimidazolylmethyl, oxadiazolylmethyl, oxadiazolylmethyl, thiadiazolylmethyl, thiadiazolylethyl, triazolylmethyl, triazolylethyl. , tetrazolylmethyl, tetrazolyl ethyl, pyridinylmethyl, pyridinylethyl, pyridazinylmethyl, pyrimidinylmethyl, pyrazinylmethyl, quinolinylmethyl, isoquinolinylmethyl and quinoxalinylmethyl.

Examples of heterocycloC3-7alkyl include, for example, azetidinyl, pyrrolidinyl, piperidinyl, perhydroazepinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, imidazolinyl, pyrrolidin-2-one, piperidin-2-one, and thiomorpholinyl.

The term "N-heterocycloC4-7alkyl" describes non-aryl heterocyclic compounds with 3-6 carbon atoms and one nitrogen atom forming a ring. Examples include azetidinyl, pyrrolidinyl, piperidinyl, and perhydroazepinyl.

Examples of aryl(C 1-6 )alkyl include, for example, phenyl(C 1-6 )alkyl, and naphthyl(-C 1-6 )alkyl.

Examples of heterocycloC3-7alkylcarbonyl(C1-6)alkyl include, for example, azetidinylcarbonyl(C1-6)alkyl, pyrrolidinylcarbonyl(C1-6)alkyl, piperidinylcarbonyl(C1-6)alkyl, piperazinylcarbonyl(C1-6)alkyl , morpholinylcarbonyl(C1-6)alkyl, and thiomorpholinylcarbonyl(C1-6)alkyl.

The term "amine", unless otherwise indicated, includes primary, secondary and tertiary amines.

Unless otherwise indicated, the term "carbamoyl" includes -NHC(O)OC1-C4alkyl, and -OC(O)NHCl-C4alkyl.

The term "halogen" includes fluorine, chlorine, bromine and iodine atoms.

The term "optionally substituted" includes both substituted and unsubstituted. Thus, for example, an optionally substituted aryl may represent a pentafluorophenyl or a phenyl ring. Furthermore, the substitution can be on any of the groups. For example, substituted aryl(C 1-6 )alkyl includes substitution on the aryl group as well as substitution on the alkyl group.

The term "oxide" of a heteroaryl group is used in the well-known chemical sense and includes, for example, N-oxides of nitrogen heteroatoms.

The compounds described herein contain one or more double bonds and may therefore give cis/trans isomers as well as other conformational isomers. The subject invention includes all such possible isomers as well as mixtures of such isomers.

The compounds described herein may contain one or more asymmetric centers and may therefore give diastereomers and optical isomers. The subject invention encompasses all such possible diastereomers, as well as their racemic mixtures, their mostly pure dissolved enantiomers, all possible geometric isomers, and their pharmaceutically acceptable salts. The above Formula I is shown without certain stereochemistry at some positions. The subject invention includes all stereoisomers of Formula I and its pharmaceutically acceptable salts. Furthermore, mixtures of stereoisomers as well as isolated specific stereoisomers are also included. During the synthetic procedures used in the preparation of such compounds, or using racemization or epimerization - procedures known to those skilled in the art, the products of such procedures may be mixtures of stereoisomers.

The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the compound of the present invention is acidic, the corresponding salt may be conveniently prepared from a pharmaceutically acceptable non-toxic base, including inorganic and organic bases. Salts derived from such inorganic bases include aluminum, ammonium, calcium, cupric, cupric, ferrous, ferric, lithium, magnesium, manganese and manganese, potassium, sodium, zinc and similar salts. Particularly preferred are ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, as well as cyclic amines and substituted amines, such as naturally occurring cyclic and synthesized substituted amines. Other pharmaceutically acceptable organic non-toxic bases from which salts can be formed include ionic exchange resins such as, for example, arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylarnine, 2-diethylaminoethanol, 2- dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resin, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and similar.

When the compound of the present invention is a base, the corresponding salts may be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, formic, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucinic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulphonic acid and the like, particularly preferred are benzenesulfonic, humic, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.

The pharmaceutical preparations of the present invention contain the compound represented by formula I (or its pharmaceutically acceptable salts) as an active ingredient, a pharmaceutically acceptable carrier and optionally other therapeutic ingredients or adjuvants. Such additional therapeutic ingredients include, for example, i) leukotriene receptor antagonists, ii) leukotriene biosynthesis inhibitors, iii) corticosteroids, iv) H1 receptor antagonists, v) beta 2 adrenoceptor agonists, vi) COKS-2 selective inhibitors, vii) statins, viii) non-steroidal anti-inflammatory drugs ("NSAIDs"), and ix) M2/M3 antagonists. The compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most convenient route in each case will depend on the host, and the nature and severity of the condition for which the active ingredient is being administered. The pharmaceutical preparations may be conveniently prepared in the form of unit doses and prepared by any of the methods known in the pharmaceutical art.

Creams, ointments, jellies, solutions, or suspensions containing a compound of Formula I may be used for topical application. Mouth and throat rinses are encompassed as topical use for the purposes of this invention.

Dosage levels from about 0.001mg/kg to about 140mg/kg of body weight per day are useful in the treatment of conditions such as i) lung disorders such as asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), respiratory disorder syndrome in adults , respiratory distress syndrome in children, cough, chronic obstructive pulmonary disease in animals, respiratory distress syndrome in adults, and respiratory distress syndrome in children, ii) gastrointestinal disorders such as ulcerative colitis, Crohn's disease, and gastric acid hypersecretion, iii ) infectious diseases such as bacterial, fungal or viral sepsis or septic shock, endotoxic shock (and related conditions such as laminitis and colic in horses), and septic shock, iv) neurological disorders such as spinal cord injuries, head injuries , neurogenic inflammation, pain, and brain reperfusion injuries, v) inflammatory disorders such as psoriatic arthritis, rheumatic arthritis, ankylosis sp ntilitis, osteoarthritis, inflammation and cytokine-mediated chronic tissue degeneration, vi) allergic disorders such as allergic rhinitis, allergic conjunctivitis, and eosinophilic granuloma, vii) psychiatric disorders such as depression, memory impairment, and monopolar depression, viii) neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, acute and chronic multiple sclerosis, ix) Dermatological disorders such as psoriasis and other benign or malignant proliferative skin diseases, atopic dermatitis, and urticaria, x) oncological diseases such as cancer, tumor growth and cancerous invasion of normal tissue, xi) metabolic disorders such as diabetes insipidus, xii) bone disorders such as osteoporosis, xiii) cardiovascular disorders such as arterial restenosis, arteriosclerosis, myocardial reperfusion injury, and xiv) other disorders such as chronic glomerulonephritis , vemal conjunctivitis, rejection of transplants and implants, and cachex ija - which are responsive to PDE4 inhibition, or alternatively about 0.05mg to about 7g per patient per day. For example, inflammation can be effectively treated by administering from about 0.01mg to about 50mg of the compound per kilogram of body weight per day, or alternatively from about 0.5mg to about 2.5g per patient per day. Furthermore, it is understood that the PDE4 inhibiting compounds of the present invention may be administered at prophylactically effective dosage levels to prevent the aforementioned conditions.

The amount of active ingredient that can be combined with the carrier materials to form a unit dosage form will vary depending on the host treated and the specific route of administration. For example, a formulation intended for oral administration to humans may suitably contain from about 0.5mg to about 5g of active agent, with a corresponding suitable amount of carrier material which may vary from about 5 to about 95 percent of the total composition. Unit dosage forms generally contain between about 0.01mg to about 1000mg of active ingredient, typically 0.01mg, 0.05mg, 0.25mg, 1mg, 5mg, 25mg, 50mg, 100mg, 200mg, 300mg, 400mg, 500mg, 600mg, 800mg or 1000mg.

It is understood, however, that specific dosage levels for each individual patient depend on a variety of factors, including age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combinations, and severity of the specific disease being treated.

In practice, the compounds of this invention represented by formula I, or its pharmaceutically acceptable salts, can be combined as active ingredients in a mixture with a pharmaceutical carrier, according to conventional pharmaceutical technique. Carriers can be of different forms, depending on the desired form of administration of the preparation, eg oral or parenteral (including intravenous). Therefore, the pharmaceutical preparations of the present invention can be prepared as discrete units suitable for oral administration such as capsules, pills or tablets, which contain a predetermined amount of the active ingredient. Furthermore, the preparations can be prepared as a powder, granules, solution, suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion, or as a water-in-oil emulsion. In addition to the usual dosage forms described above, the compound represented by formula I, or its pharmaceutically acceptable salts, can be administered by controlled release and/or through delivery devices. Preparations can be prepared by any of the pharmaceutical methods. In general, such methods include a step that brings the active ingredient into contact with a carrier, which consists of one or more of the necessary ingredients. In general, the compositions are prepared by uniformly and thoroughly mixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be suitably shaped.

Therefore, the pharmaceutical compositions of this invention may contain a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt of Formula I. The compounds of Formula I, or a pharmaceutically acceptable salt thereof, may also be included in the pharmaceutical compositions in combination with one or more other therapeutically active compounds.

Pharmaceutical carriers that may be used are, for example, solid, liquid, or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers are sugar syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen.

In the preparation of the composition for the oral dosage form, all suitable pharmaceutical media can be used. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like may be used to produce oral liquid preparations, such as suspensions, elixirs, and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used to provide oral solid preparations such as powders, capsules and tablets. Tablets and capsules are preferred oral unit doses, for ease of administration, when solid pharmaceutical carriers are used. Optionally, the tablets can be coated using standard aqueous or anhydrous techniques.

A tablet containing the compositions of this invention may be prepared by compression or in a mold, optionally with one or more additional ingredients or adjuvants. Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in free form, such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surfactant or dispersing agent. Tablets from the mold can be prepared in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. Each tablet preferably contains from about 0.1mg to about 500mg of active ingredient and each pill or capsule preferably contains from about 0.1mg to about 500mg of active ingredient.

Pharmaceutical preparations of the present invention suitable for parenteral administration can be prepared as solutions or suspensions of the active compound in water. A suitable surfactant may be included, such as, for example, hydroxypropyl cellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycol, and their mixtures in oil. Furthermore, a preservative may be included to prevent the harmful growth of microorganisms.

Pharmaceutical preparations of the present invention suitable for injectable use contain a sterile aqueous solution or dispersion. Furthermore, the preparations can be in the form of sterile powders for the ad hoc preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be an effective fluid for easy syringability. Pharmaceutical preparations must be stable during production and storage; therefore, protection against the contaminating action of microorganisms, such as bacteria and fungi, is desirable. Carriers can be a solvent or dispersing medium, containing, for example, water, ethanol, polyol (eg, glycerol, propylene glycol, and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

The pharmaceutical preparations of the subject invention can be in a form suitable for local use, such as, for example, an aerosol, cream, ointment, lotion, powder, or the like. Furthermore, the compositions may be in a form suitable for use in transdermal devices. These formulations may be prepared using a compound represented by formula I of the present invention, or a pharmaceutically acceptable salt thereof, by conventional process methods. As an example, a cream or ointment is prepared by mixing hydrophilic materials and water, together with about 5% by weight to about 10% by weight of the compound, to obtain a cream or ointment of the desired consistency.

The pharmaceutical compositions of this invention may be in a form suitable for rectal administration, where the carrier is a solid. Preferably, the mixture forms suppository unit doses. Suitable carriers include coconut butter and other materials commonly used in the art. Suppositories may be conveniently prepared by first mixing the composition with the softened or dissolved carrier(s) while cooling and forming in molds.

In addition to the previously mentioned carrier ingredients, the pharmaceutical formulations described above may conveniently contain one or more additional carrier ingredients, such as diluents, buffers, flavoring agents, binders, surfactants, thickening agents, lubricants, preservatives (including antioxidants ) and similar. Furthermore, other adjuvants may be included to make the formulation isotonic with the blood of the recipient. Preparations containing the compound described by formula I, or its pharmaceutically acceptable salt, can also be prepared in the form of a powder or liquid concentrate.

The compounds and pharmaceutical compositions of the present invention exhibit biological activity as PDE4 inhibitors. Accordingly, another aspect of the invention is the treatment of mammals, for example, i) pulmonary disorders such as asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome, pediatric respiratory distress syndrome, cough, chronic obstructive pulmonary disease disease in animals, respiratory distress syndrome in adults, and respiratory distress syndrome in children, ii) gastrointestinal disorders such as ulcerative colitis, Crohn's disease, and hypersecretion of gastric acid, iii) infectious diseases such as bacterial, fungal or viral sepsis or septic shock, endotoxic shock (and related conditions such as laminitis and colic in horses), and septic shock, iv) neurological disorders such as spinal cord injuries, head injuries, neurogenic inflammation, pain, and reperfusion injuries of the brain, v ) inflammatory disorders such as psoriatic arthritis, rheumatic arthritis, ankylosing spondylitis, osteoarthritis, inflammatory and cytokine -mediated chronic tissue degeneration, vi) allergic disorders such as allergic rhinitis, allergic conjunctivitis, and eosinophilic granuloma, vii) psychiatric disorders such as depression, memory impairment, and monopolar depression, viii) neurodegenerative disorders, such as Parkinson's disease, Alzheimer's disease, acute and chronic multiple sclerosis, ix) dermatological disorders such as psoriasis and other benign or malignant proliferative skin diseases, atopic dermatitis, and urticaria, x) oncological diseases such as cancer, tumor growth and cancerous invasion normal tissue, xi) metabolic disorders such as diabetes insipidus, xii) bone disorders such as osteoporosis, xiii) cardiovascular disorders such as arterial restenosis, arteriosclerosis, myocardial reperfusion injury, and xiv) other disorders, such as chronic glomerulonephritis, vemal conjunctivitis, rejection of transplants and implants, and cachexia - underlying diseases not improving by inhibiting the PDE4 isoenzyme, and the resulting elevated cAMP levels - by administering an effective amount of the compounds of this invention. The term "mammals" includes humans as well as other animals such as, for example, dogs, cats, horses, pigs, and livestock. Accordingly, it is understood that the treatment of mammals in addition to humans is the treatment of clinically correlated diseases to those listed above in the human disease examples.

Furthermore, as described above, the compounds of this invention may be used in combination with other therapeutic compounds. In particular, combinations of the PDE4 inhibiting compound of the present invention can be used in combination with i) leukotriene receptor antagonists, ii) leukotriene biosynthesis inhibitors, iii) COKS-2 selective inhibitors, iv) statins, v) NSAIDs, vi) M2/M3 antagonists, vii ) corticosteroids, viii) H1 antagonists (histamine) receptors and ix) beta 2 adrenoceptor agonists.

Therefore, for example, lung disorders such as asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome, pediatric respiratory distress syndrome, cough, animal chronic obstructive pulmonary disease, adult respiratory distress syndrome, and respiratory disorder syndrome in children can be suitably treated with capsules, pills or tablets, which can contain mg, 5mg, 25mg, 50mg, 100mg, 200mg, 300mg, 400mg, or 500mg of the active ingredient of the compound of the subject application, or its pharmaceutically acceptable salts, given once, twice, or thrice a day.

Gastrointestinal disorders such as ulcerative colitis, Crohn's disease, and gastric acid hypersecretion can be conveniently treated with capsules, pills, or tablets containing 1 mg, 5 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, or 500 mg of the active ingredient of the subject application compound. , or its pharmaceutically acceptable salts, administered once, twice, or three times a day.

Infectious diseases such as bacterial, fungal or viral sepsis or septic shock, endotoxic shock (and related conditions such as laminitis and equine colic), and septic shock can be conveniently treated with capsules, pills or tablets containing 1mg, 5mg, 25mg, 50mg, 100mg, 200mg) 300mg, 400mg, or 500mg of the active ingredient of the compound of the subject application, or its pharmaceutically acceptable salt, administered once, twice, or three times a day.

Neurological disorders such as spinal cord injuries, head injuries, neurogenic inflammation, pain, and brain reperfusion injuries can be conveniently treated with capsules, pills or tablets, containing 1mg, 5mg, 25mg, 50mg, 100mg, 200mg, 300mg, 400mg, or 500 mg of the active ingredient of the compound of the subject application, or its pharmaceutically acceptable salt, administered once, twice, or three times a day.

Inflammatory disorders, such as psoriatic arthritis, rheumatic arthritis, ankylosing spondylitis, osteoarthritis, inflammation and cytoficin-mediated chronic tissue degeneration can be conveniently treated with capsules, pills or tablets, containing 1mg, 5mg, 25mg, 50mg; 100mg, 200mg, 30Gmg, 400mg, or 500mg of the active ingredient of the compound of the subject application, or its pharmaceutically acceptable salt, administered once, twice, or three times a day.

Allergic disorders such as allergic rhinitis, allergic conjunctivitis, and eosinophilic granuloma can be conveniently treated with capsules, pills, or tablets containing 1 mg, 5 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, or 500 mg of the active ingredient of the subject compound. application, or its pharmaceutically acceptable salts, administered once, twice, or three times a day.

Psychiatric disorders such as depression, memory impairment, and monopolar depression may be conveniently treated with capsules, pills, or tablets containing 1mg, 5mg, 25mg, 50mg, 100mg, 200mg, 300mg, 400mg, or 500mg of the active ingredient of the subject application compound, or its pharmaceutically acceptable salts, administered once, twice, or thrice daily.

Neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, acute and chronic multiple sclerosis can be conveniently treated with capsules, pills or tablets, containing 1mg, 5mg, 25mg, 50mg, 100mg, 200mg, 300mg, 400mg, or 500mg. of the active ingredient of compound a of the subject application, or its pharmaceutically acceptable salt, administered once, twice, or three times a day.

Dermatological disorders such as psoriasis and benign or malignant proliferative skin diseases, atopic dermatitis, and urticaria can be appropriately treated with capsules, pills, or tablets, containing 1mg, 5mg, 25mg, 50mg, 100mg, 200mg, 300mg, 400mg, or 500mg of active an ingredient of the compound of the subject application, or its pharmaceutically acceptable salt, administered once, twice, or three times a day.

Oncological diseases such as cancer, tumor growth and cancerous invasion of normal tissue can be conveniently treated with capsules, pills or tablets, containing 1mg, 5mg, 25mg, 50mg, 100mg, 200mg, 300mgs 400mg, or 500mg of the active ingredient of the compound of the subject application, or its pharmaceutically acceptable salts, administered once, twice, or thrice daily.

Metabolic disorders such as diabetes insipidus can be conveniently treated with capsules, pills or tablets, containing 1mg, 5mg, 25mg, 50mg, 100mg, 200mg, 300mg, 400mg, or 500mg of the active ingredient of the compound of the subject application, or its pharmaceutically acceptable salt. , given once, twice, or three times a day.

Bone disorders such as osteoporosis, cardiovascular disorders such as arterial restenosis, arteriosclerosis, myocardial reperfusion injury, and therapeutic disorders such as chronic glomerulonephritis, vernal conjunctivitis, graft and implant rejection, and cachexia may be appropriately treated with capsules, pills, or tablets. containing 1 mg, 5 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, or 500 mg of the active ingredient of the compound of the subject application, or its pharmaceutically acceptable salt, administered once, twice, or three times a day.

The abbreviations used here are shown in the tables and have the following meanings. Abbreviations not shown below have meanings that are most commonly used, unless otherwise indicated by the verb.

[image]

ALKYL GROUP ABBREVIATIONS

[image]

TESTS THAT PROVE BIOLOGICAL ACTIVITY

LPS IFMLP-INDUCED TNF-α ILTB4 ASSAYS IN HUMAN WHOLE BLOOD

Whole blood provides a protein- and cell-rich medium suitable for studying the biochemical efficacy of anti-inflammatory compounds, such as PDE4-selective inhibitors. Normal non-stimulated human blood does not contain detectable levels of TNF-α and LTB4. After stimulation with LPS, activated monocytes express and secrete TNF-α for up to 8 hours and the plasma level remains stable for 24 hours. Published studies show that inhibition of TNF-α by increasing intracellular cAMP via PDE4 inhibition and/or enhanced adenylyl cyclase activity takes place at the transcriptional level. LTB4 synthesis is also sensitive to intracellular cAMP levels and can be completely inhibited by PDE4-selective inhibitors. As little LTB4 is produced during 24 h LPS stimulation of whole blood, additional LPS stimulation of fMLP-induced human whole blood is required for activated neutrophils to synthesize LTB4. Therefore, using the same blood sample it is possible to evaluate the potency of the compound on two surrogate markers of PDE4 activity in whole blood by the following procedure.

Fresh blood was collected in heparinized tubes by venipuncture of healthy human volunteers (men and women). These subjects had no visible inflammatory conditions and had not taken NSAIDs for at least 4 days before blood collection. A 500μL aliquot of blood was pre-incubated with either 2μL of vehicle (DMSO) or 2μL of test compound at various concentrations, for 15 minutes at 37°C. This was followed by the addition of 10 μL of vehicle (PBS) as a blank or 10 μL of LPS (1 μg/mL final concentration, #F-2630 (Sigma Chemical Co., St. Lom's, MO)) from E. coli, serotype 0111 :B4; diluted in 0.1 % w/v BSA (in PBS)). After 24 hours of incubation at 37°C, 10μL of PBS (blank) or 10μL of LPS (1μg/mL final concentration) was added to the blood and incubated for 30 minutes at 37°C. Blood was then stimulated with 10μL PBS (blank) or 10μL fMLP (1μM final concentration, #F-3506 (Sigma); diluted in 1% w/v BSA (in PBS)) for 15 minutes at 37°C. Blood samples were centrifuged at 1500xg for 10 minutes at 4°C to obtain plasma. A 50μL aliquot of plasma was mixed with 200μL of methanol to precipitate the proteins and centrifuged as above. The supernatant was tested for LTB4 using an enzyme-linked immunosorbent assay kit (#520111 Cayman Chemical Co., Ann Arbor, MI) according to the manufacturer's procedure. TNF-α was assayed in diluted plasma (in PBS) using an ELISA kit (Cistron Biotechnology, Pine Brook, NJ) according to the manufacturer's procedure. IC50 values should be less than about 5μM, preferably less than about 2.5μM. IC50 values in Examples 1 to 33 varied from 0.01 μM to 2.4 μM.

ANTI-ALLERGIC ACTIVITY IN VIVO

The compounds of the invention were tested for activity on IgE-mediated allergic lung inflammation, induced by antigen inhalation, in a sensitized guinea pig. Guinea pigs were sensitized to ovalbumin under mild immunosuppression, induced by cyclophosphamide, by intraperitoneal injection of antigen in combination with aluminum hydroxide and pertussis vaccine. High doses of antigen were administered two and four weeks later. After six weeks, the animals were stimulated with ovalbumin in aerosol form, while they were protected with an intraperitoneally administered anti-histaminic agent (mepyramine). After a further 48 hours, bronchial alveolar lavage (BAL) was performed and the number of eosinophils and leukocytes in the BAL fluid was measured. Lungs were also removed for histological examination of inflammatory damage. Administration of the compounds from the Example (0.001-10mg/kg i.p. or p.o.), up to three times during 48h after antigen challenge, led to a significant reduction of eosinophilia and accumulation of other inflammatory leukocytes.

SPA BASED PDE ACTIVITY TEST PROTOCOL

Compounds that inhibit the hydrolysis of cAMP to AMP by type-FV cAMP-specific phosphodiesterases were screened in a 96-well plate as follows:

Test compound (dissolved in 2μL DMSO), 188μL substrate buffer, containing [2,8-3H] adenosine 3',5'-cyclic phosphate (cAMP, 100nM to 50μM), was added to a 96-well plate at 30°C. 10 mM MgCl2, 1 mM EDTA, 50 mM Tris, pH 7.5.

The reaction was initiated by the addition of human recombinant PDE4 (the amount was controlled so that -10% of the product was prepared in 10 min.), the reaction was stopped after 10 min. by the addition of 1 mg of PDE-SPA beads (Amersham Pharmacia Biotech, Inc., Piscataway, NJ ), the resulting AMP product was quantified on a Wallace Microbeta® plate counter (EG&G Wallace Co., Gaithersburg, MD). The signal in the absence of enzyme was defined as background. 100% activity was defined as the signal detected in the presence of enzyme and DMSO with background subtracted. Accordingly, the percentage of inhibition was calculated. The IC50 value was approximated with non-linear regression, using a standard 4-parameter/multiple binding site ten-point titration equation.

The IC 50 values of EXAMPLES 1 through 33 were determined with 100 nM cAMP using a purified GST fusion protein of human recombinant phosphodiesterase IVa (met-248) produced by the baculovirus/Sf-9 expression system. IC50 values should be less than about 1000nM, preferably less than about 250nM, and even more preferably less than about 100nM. The IC50 values of EXAMPLES 1 through 33 varied from 0.1 nM to 90.0 nM.

The following examples are intended to illustrate certain preferred implementations of the invention and no limitation on the scope of the invention is implied.

Unless otherwise indicated, the experimental procedures were prepared under the following conditions. All operations were performed at room or ambient temperature - which is in the range of 18-25°C. Solvent evaporation was performed using a rotary evaporator under reduced pressure (600-4000 pascals: 4.5-30 mm Hg) with a bath temperature of up to 60°C. The course of the reactions was monitored by thin layer chromatography (TLC) and the reaction times are given as an illustration only. Melting points are uncorrected and "d" indicates decomposition. Melting points are those obtained for materials prepared as described. Polymorphism may result in the isolation of materials with different melting points in some preparations. The structure and purity of all final products is ensured by at least one of the following techniques: TLC, mass spectrometry, nuclear magnetic resonance (NMR) spectrometry or microanalytical data. The yields given are for illustration purposes only. NMR data are given as delta (δ) values of large diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, determined at 300 MHz, 400 MHz, or 500 MHz using the indicated solvent. Conventional abbreviations used for the signal shape are: s, singlet; d. doublet; t. triplet; m. multiplet; no. wide; etc. Additionally, "Ar" indicates an aromatic signal. Chemical symbols have the usual meanings; the following abbreviations are also used: v (volume), w (weight), b.p. (boiling point), m.p. (melting point), L (Htra(s)),mL (milliliters), g (gram(s)), mg (milligram(s)), mol (moles), mmol (millimoles), eq (equivalent(s) ).

Methods of Synthesis

The compounds of the subject invention can be prepared by the following methods, Substituents are the same as in Formula I, except where defined otherwise.

In the first method described below in Scheme 1, an appropriately substituted ethyl 2-chloronicotinoyl acetate derivative of formula II is reacted with 1.5 equivalents of triethyl orthoformate and 5 equivalents of acetic anhydride at 130°C, and after removal of the unstable components the crude 2-chloronicotinoyl acrylate of formula III is immediately reacted with 1.2 equivalents of a suitably substituted haloaryl amine of formula IV, such as, for example, 3-bromoaniline, in a halogenated hydrocarbon solvent, such as methylene chloride, at a temperature of 0°C to room temperature. After a suitable reaction time, varying from 2 to 24 hours, the resulting 3-arylamino acrylate of formula V is obtained by evaporation of the solvent and can be further purified by silica gel chromatography or crystallization from a suitable solvent. The compound of formula V may alternatively be used without further purification in the next step. Cyclization of the compound of formula V to l-haloaryl-1,4-dihydro[1,8]naphthyridin-4-one carboxylate of formula VI was achieved by treatment with a small excess of a strong base, such as an alkali metal hydride, for example sodium hydride, in a suitable solvent such as tetrahydrofuran, at an initial temperature of 0°C by warming to room temperature, if necessary, to complete the process. The product of formula VI is isolated in crude form by dilution with a large volume of water, followed by filtration or extraction with a suitable organic solvent, such as diethyl ether, ethyl acetate, or a halogenated hydrocarbon solvent, such as chloroform or methylene chloride. The product can be further purified by silica gel chromatography, crystallization or prolonged stirring in a suitable solvent followed by filtration.

The ester product of formula VI thus obtained can be hydrolyzed to the corresponding carboxylic acid derivative under basic conditions, using an aqueous solution of an alkaline base, such as alkaline carbonate or preferably sodium or potassium hydroxide, with an organic co-solvent, such as tetrahydrofuran or primary, secondary or tertiary alkanol, such as methanol or ethanol, or combinations thereof at temperatures ranging from room temperature to reflux temperature, for a suitable time. The resulting carboxylic acid is isolated in crude form, after acidification, using an aqueous solution of an inorganic acid, such as hydrochloric, sulfuric or similar acid, and by filtration or extraction with a suitable organic solvent such as diethyl ether, ethyl acetate, or a halogenated hydrocarbon solvent, such as chloroform or methylene chloride. The product can be further purified by silica gel chromatography, crystallization or prolonged stirring in a suitable solvent, followed by filtration. The carboxylic acid is then transformed into a suitable primary, secondary or tertiary amide analogue of formula VII by any general procedure known to organic chemists, preferably by initial transformation to the mixed anhydride by treatment with a small excess, usually 1.25 equivalents, of a suitable alkyl chloroformate, such as ethyl or isobutyl chloroformate, in the presence of a large excess, usually 2.5 equivalents, of a tertiary organic amine such as triethylamine or N,N-diisopropylethylamine, in an organic solvent such as tetrahydrofuran at low temperature, preferably 0°C for 30 minutes to 3 hours. Alternatively, the acid may be transformed into the acid chloride through the action of, for example, thionyl chloride. An excess, usually 5 or more equivalents, of a suitable primary or secondary amine or aqueous ammonium hydroxide solution is added and the reaction allowed to take place at a temperature varying from 0°C to room temperature for a suitable time, usually 1-24 hours. The desired amide of formula VII is isolated in crude form by precipitation with water and filtration or extraction with a suitable organic solvent such as diethyl ether, ethyl acetate, or a halogenated hydrocarbon solvent such as chloroform or methylene chloride. The product can be further purified by silica gel chromatography, crystallization or prolonged stirring in a suitable solvent, followed by filtration. Alternatively, the amide of formula VII can be prepared from an acid and an amine via a suitable coupling reagent, such as carbonyldiimidazole (CDI). In cases where the amide moiety is 2,6-dichloropyridin-4-yl, a different procedure is used in which the 4-amino-3,5-dichloropyridine anion is generated at low temperature, preferably 0°C, using a strong alkaline hydride, such as sodium hydride in a solvent such as tetrahydrofuran, and by reaction with the acid chloride of a carboxylic acid (from the hydrolysis of an ester of formula VI) generated by a suitable known process, usually by the action of oxalyl chloride activated by a catalytic amount of N,N-dimethylformamide in a solvent such as tetrahydrofuran.

For the synthesis of compounds of formula I, the amide of a compound of formula VII is reacted with an appropriately substituted acetylene of formula VIII under transition metal catalysis such as bis(triphenylphosphine)palladium(H) chloride or [1,1'-bis(diphenylphosphmo)ferrocene]dichloropalladium(H) in a suitable solvent such as THF or DMF, in the presence of triethylamine and a copper salt such as copper iodide, at a temperature varying from room temperature to reflux for a suitable period of time. Alternatively, an ester of a compound of formula VI may be reacted in the same manner to give an ester of a compound of formula IX, which is subjected to the hydrolysis and amidation processes described above, leading to a compound of formula I.

[image]

In another approach to the synthesis of compounds of formula I, described below in Scheme 2, an amide of formula VII is reacted with trimethylsilylacetylene catalyzed by transition metals such as bis(triphenylphosphine)palladium(II) chloride or [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) in a suitable solvent, such as THF or DMF, in the presence of triethylamine and a copper salt, such as copper iodide, at a temperature varying from room temperature to reflux, for a suitable period of time. The resulting compound is deprotected by the TMS protecting group under the action of an aqueous alkaline hydroxide solution, such as sodium or potassium hydroxide in the presence of an organic co-solvent such as methanol, or alternatively by treatment with a fluoride source, such as tetrabutylammonium fluoride in THF solution, to give an acetylene derivative of formula X.

Such a compound is reacted with a suitable alkyl or aryl or heteroaryl halide of formula XI under the catalysis of transition metals such as bis(triphenylphosphine)palladium(H) chloride or [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) in a suitable solvent as which are THF or DMF, in the presence of triethylamine and a copper salt, such as copper iodide, at a temperature varying from room temperature to reflux, for a suitable period of time, to give a compound of formula I. Alternatively, the ester of a compound of formula VI may be processed in the same way, to obtain the ester of the compound of formula IX, which is subjected to the hydrolysis and amidation process, described above, leading to the compound of formula I.

[image]

In an alternative approach, the acetylenic esters of formula IX or XII (where R 8 = H) described in Scheme 3 are reacted with a suitably substituted 2-chloronicotinoyl chloride of formula XIII with a 3-dialkylaminoacrylate, for example ethyl 3-dimethylaminoacrylate, in the presence of a tertiary amine, such as is triethylamine in a solvent such as toluene at a suitable temperature to give the 3-dialkylamino acrylate of formula XIV. Such a substance is reacted with an appropriately substituted 3-aminophenylacetylene derivative of formula XV, in a solvent such as DMF or acetonitrile, in the presence of an inorganic base, such as potassium carbonate, at a suitable temperature, to give an acetylenic ester of formula IX or XII (where R8 = H ).

[image]

Most of the acetylenic reagents of formula VIII used in this invention are from commercial sources. Where necessary, suitably substituted acetylenes of formula VIII are synthesized as described in Scheme 4, preferably from the corresponding halides (XI) by initial condensation with trimethylsilylacetylene, under transition metal catalysis, followed by removal of the TMS group, as described in Preparation Scheme 2 above compounds of type X or XII. When the R8 substituent is an acetylene secondary or tertiary alcohol, the trimethylsilylacetylene anion is generated at low temperature, using an alkyllithium base such as n-butyllithium, and can be reacted with an appropriately substituted aldehyde or ketone to give the desired reagent of formula VIII.

[image]

The following are examples of the synthesis of aryl and heteroaryl halides, corresponding to compounds of formula XI bearing a secondary or tertiary alcohol substituent. For the pyridine derivative (Scheme 5), the halogen-substituted pyridyl carboxylate of formula XVI can be reacted with organometallics such as Grignard reagents to give the tertiary alcohol of formula XVII. Alternatively, the dibromopyridine substrate of formula XVIII may be monometalated using an alkyllithium species, such as n-butyllithium, followed by addition of an aldehyde or ketone, to give a compound of formula XVII.

[image]

A thiophene derivative of formula XX results from the reaction of a halogen-substituted thiophene aldehyde or ketone of formula XIX (Scheme 6) with an organometallic species such as a Grignard reagent.

[image]

For the synthesis of thiazole derivatives of formula XXII, described in Scheme 7, initial metalation of the thiazole, using an alkyllithium such as n-butyllithium, followed by addition of an aldehyde or ketone gives the 2-thiazolyl secondary or tertiary alcohol that is suitably protected, for example as the SEM ether of formula XXI . Further bromination leads to the introduction of a bromo atom at the 5-position with simultaneous removal of the protecting group, resulting in the compound of formula XXII.

[image]

Where necessary, the pyridine derivatives can be oxidized to the corresponding N-oxides, using well-known reagents, such as m-chloroperoxybenzoic acid or magnesium monoperoxyphthalate.

EXAMPLES

With reference to the formula below, Examples 1-33 are shown in TABLE 1 below.

[image]

TABLE 1

[image]

[image]

[image]

With reference to the formula below, Examples 1-33 are shown in TABLE 2 below.

[image]

TABLE 2:

[image]

[image]

EXAMPLE 1

N-isopropyl-1-[3-(phenylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxaniide

Step 1: Ethyl 3-(3-bromoanilino)-2-(2-chloronicotinoyl) acrylate.

A mixture of ethyl 2-chloronicotinoyl acetate (41.1g, 180.5mmol), triethyl orthoformate (40.12g, 271mmol) and acetic anhydride (92.05g, 902.5mmol) was heated at 130°C for 2.5 hours. Unstable components were distilled off and the resulting residue was evaporated twice using xylene. The oily residue was dissolved in methylene chloride (250 mL) and 3-bromoaniline (37.25 g, 216.6 mmol) was slowly added. The resulting solution was stirred at room temperature for 18 hours, and the solvent was evaporated. The resulting crude compound was used as such in the next step.

Step 2: Ethyl 1-(3-bromophenyl)-1,4-dihydro[1.8]naphthyridin-4-one-3-carboxylate.

The crude compound from Step 1 was dissolved in tetrahydrofuran (500mL), the solution was cooled to 0°C, and sodium hydride (as a 60% dispersion in oil, 9.4g, 235mmol) was added portionwise. After stirring at 0° for 1 hour, the resulting mixture was allowed to warm to room temperature. After 2 hours, water (400 mL) was added to the resulting suspension and the undissolved solid was filtered and washed with water. The dried solid was stirred in ether (150mL) at room temperature for 24 hours, and filtered to give the ethyl 1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxylate compound. as a cream-colored solid.

1H NMR (acetone-de) δ 1.32 (t, 3H), 4.29 (q, 2H), 7.54-7.63 (m, 2H), 7.69 (dd, 1H), 7.7S (dd, 1H), 7.93 (s, 1H), 8.66-8.71 (m, 3H).

Step 3: 1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxylic acid.

A suspension of ethyl 1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxylate from Step 2 (52.5 g, 140.7 mmol) in a mixture of tetrahydrofuran (400 mL), methanol (400 mL) and 1N aqueous sodium hydroxide (280mL) was heated to 50°C with stirring for 20 minutes. After cooling, the mixture was diluted with water (300 mL) and 1N aqueous HCl (325 mL) was added. After stirring for 45 minutes, the precipitate was filtered off, washed well with water and dried to give 1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxylic acid as a crimson solid .

1H NMR(acetone-d6) δ 7.65 (t, 1H), 7.76 (m, 2H), 7.84 (d, 1H), 7.99 (s, 1H), 8.87 (m, 2H), 9.01 (s, 1H).

Step 4: N-isopropyl-1-(3-bromophenin-1,4-dihydro[1,81-naphthyridin-4-one-3-carboxamide.

To a suspension of 1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxylic acid from Step 3 (26.3g, 76mmol) and triethylamine (23.2g, 230mmol) in tetrahydrofuran ( 1000mL) at 0°C, isobutyl chloroformate (l 8.85g, 138mmol) was added. After stirring at 0°C for 2 hours, isopropylamine (23g, 390mmol) was added and the mixture was allowed to warm to room temperature and stirred overnight. The mixture was then partitioned between ethyl acetate and water, the organic phase was dried and evaporated to a solid, which was stirred in ether at room temperature for 3 hours and filtered to give N-isopropyl-1-(3-bromophenyl)- 1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide as a white solid.

1H NMR (acetone-d6) δ 1.25 (d, 6H), 4.17 (m, 1H), 7.59-7.63 (m, 2H), 7.70 (d, 1H), 7.80 (d, 1H), 7.94 (s, 1H), 8.73 (m, 1H), 8.78 (d, 1H), 8.85 (s, 1H), 9.61 (br, MH).

Step 5: N-isopropyl-1-[(3-phenylethynyl)phenyl]-1,4-dihydro[1,81-naphthyridin-4-one-3-carboxamide.

A mixture of the amide from Step 4, phenylacetylene (1.9 eq), triethylamine (1.6 eq), triphenylphosphine (0.06 eq) and bis(triphenylphosphine)palladium(II) chloride (0.05 eq) in THF (16mL/mmol) was stirred at room temperature for 20 minutes. Copper (I) iodide (5 mg/mmol) was added and the mixture was stirred at reflux for 18 hours. After cooling, the mixture was quenched with saturated aqueous ammonium chloride solution and partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulfate and the crude product was chromatographed on silica gel, eluted with a 1:9 mixture of ether and methylene chloride, to give a solid, which was stirred in ether at room temperature and filtered to give N-isopropyl- 1-[(3-phenylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide compound, as a solid.

1H NMR (acetone-d6) δ 1.24 (d, 6H), 4.18 (m, 1H), 7.42 (m, 3H), 7.56-7.61 (m, 3H), 7.69 (m, 2H), 7.76 (m, 1H ), 7.85 (s, 1H), 8.73 (m, 1H), 8.77 (dd, 1H), 8.88 (s, 1H), 9.62 (br, NH).

EXAMPLE 2

N-isopropyl-[3-(2-pyridinyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide

After applying the procedure of Step 5 of EXAMPLE 1, substituting 2-ethynylpyridine for phenylacetylene, the title compound was obtained as a brown solid.

1H NMR(acetone-d6) δ 1.25 (d, 6H), 4.18 (m, 1H), 7.38 (m, 1H), 7.59-7.64 (m, 2H), 7.71-7.76 (m, 2H), 7.81-7.85 (m, 2H), 7.92 (s, 1H), 8.61 (m, 1H), 8.74 (m, 1H), 8.7S (dd, 1H), 8.89 (s, 1H), 9.62 (br, NH) .

EXAMPLE 3

N-isopropyl-1-[3-(4-pyridinylmethyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide

After applying the procedure of Step 5 of EXAMPLE 1, but substituting 4-ethynylpyridine (J.Org.Chem. 1996, 61, 6535) for phenylacetylene, the title compound was obtained as a solid,

1H NMR (acetone-d6) δ 1.24 (d, 6H), 4.18 (m, 1H), 7.49 (m, 2H), 7.61 (m, 1H), 7.71-7.78 (m, 2H), 7.81 (m, 1H ), 7.92 (s, 1H), 8.62 (m, 2H), 8.73 (m, 1H), 8.78 (dd, 1H), 8.87 (s, 1H), 9.62 (br, NH).

EXAMPLE 4

N-isopropyl-1-[3-(1-oxido-4-pyridinylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide

In a solution of N-isopropyl-1-[3-(4-pyridinylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide from EXAMPLE 3 in methylene chloride (36mL/mmol) and magnesium monoproxyphthalate hexahydrate (MMPP, 3.6 eq) was added to methanol (3mL/mmol) and the mixture was stirred at room temperature overnight. A further amount of MMPP (2 eq) was added and stirring was continued for 24 hours. The resulting mixture was filtered through a pad of celite, the filtrate was diluted with methylene chloride and washed with aqueous sodium bicarbonate in water. After drying, the organic phase was evaporated and the crude product was purified by silica gel chromatography, eluting with 10% methanol in methylene chloride, to give the title compound as a solid.

1H NMR (CDCl3) δ 1.28 (d, 6H), 4.28 (m, 1H), 7.35 (d, 2H), 7.46 (m, 2H), 7.58 (m, 2H), 7.67 (m, 1H), 8.14 ( d, 2H), 8.69 (m, 1H), 8.81 (dd, 1H), 8.99 (s, 1H), 9.62 (br, NH).

EXAMPLE 5

N-isopropyl-1-(3-ethynylphenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxarnide

Step 1: N-isopropyl-1-[3-trimethylsilyl-ethyninphenyl]-1,4-dihydro[1,8]naphthmidine-4-one-3-carboxamide.

After applying the procedure from Step 5 of EXAMPLE 1, but substituting trimethylsilylacetylene for phenylacetylene, N-isopropyl-1-[3-(trimethylsilylethylene)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide product was obtained and used in the next step without further purification.

Step 2: N-isopropyl-1-(3-ethynylphenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide.

The crude product from Step 1 was dissolved in methanol (12mL/mmol) and 1N aqueous sodium hydroxide (3 eq) was added, forming a suspension. The suspension mixture was stirred at room temperature for 2 hours, and the methanol was evaporated. The resulting aqueous suspension was diluted with water, and the product was extracted with ethyl acetate. The crude product was chromatographed on silica gel, eluting with 10% ether in methylene chloride, to give N-isopropyl-1-(3-ethynylphenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3- carboxamide compound as a solid.

1H NMR (acetone-d6) 1.24 (d, 6H), 3.81 (s, 1H), 4.17 (m, 1H), 7.59 (m, 1H), 7.64-7.71 (m, 3H), 7.81 (s, 1H) , 8.72 (m, 1H), 8.76 (dd, 1H), 8.84 (s, 1H), 9.61 (br, NH).

EXAMPLE 6

N-cyclopropyl-1-(3-ethylphenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide

Step 1: N-cyclopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide.

After applying the procedure from Step 4 of EXAMPLE 1, but substituting cyclopropylamine for isopropylamine, N-cyclopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]nafliridin-4-one-3-carboxamide was obtained as a powder white solid.

1H NMR (acetone-d6) δ 0.59 (m, 2H), 0.80 (m, 2h), 2.96 (m, 1H), 7.59-7.68 (m, 2H), 7.72 (dd, 1H), 7.82 (dd, 1H ), 7.97 (s, 1H), 8.72-8.81 (m, 2H), 8.89 (s, 1H), 9.70 (br, NH).

Step 2 and 3: N-cyclopropyl-1-(3-ethynylphenyl)-1,4-dihydron.81-naphthyridin-4-one-3-carboxamide

After the procedures from Steps 1 and 2 of the EXAMPLE. 5, but substituting the product from Step 1 for N-isopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide, N-cyclopropyl-1-(3- ethynylphenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide compound was obtained as a solid.

1H NMR (CDCl3) δ 0.66 (m, 2H), 0.85 (m, 2H), 2.97 (m, 1H), 3.18 (s, 1H), 7.42 (d, 1H), 7.47 (m, 1H), 7.52- 7.58 (m, 2H), 7.65 (d, 1H), 8.70 (m, 1H), 8.80 (dd, 1H), 8.98 (s, 1H), 9.74 (br, NH).

EXAMPLE 7

N-isopropyl-1-[3-(3-pyridinylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide

After applying the procedure from Step 5 of EXAMPLE 1, but substituting N-isopropyl-1-(3-ethynylphenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxanidise of EXAMPLE 5 for phenylacetylene and 3-bromopyridine for N-isopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide The title compound was obtained as a light brown solid.

1H NMR (acetone-d6) δ 1.24 (d, 6H), 4.18 (m, 1H), 7.43 (m, 1H), 7.61 (m, 1H), 7.70-7.75 (m, 2H), 7.80 (d, 1H) ), 7.90 (s, 1H), 7.94 (d, 1H), 8.58 (m, 1H), 8.74-8.79 (m, 3H), 8.88 (s, 1H), 9.62 (br, NH).

EXAMPLE 8

N-isopropyl-1-[3(1-oxido-3-pyridinylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide

After applying the procedure of EXAMPLE 4, but substituting N-isopropyl-1-[3-(3-pyridinylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridm-4-one-3-carboxamidase of EXAMPLE 7 for N-isopropyl -1-[3-(4-pyridinylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide, the title compound was obtained as a solid.

1HNMR(CDCl3)δ 1.28(d, 6H), 4.28(mf 1H), 7.26(m, 1H), 7.36(d; 1H), 7.45-7.49 (m, 2H), 7.57-7.62 (m, 2H), 7.69 (d, 1H), 8.16 (d, 1H), 8.31 (s, 1H), 8.69 (m, 1H), 8.81 (dd, 1H), 8.99 (s, 1H), 9.63 (br, NH).

EXAMPLE 9

N-cyclopropyl-1-[3-(3-pyridinylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide

After applying the procedure from Step 5 of EXAMPLE 1, but substituting N-cyclopropyl-1-(3-ethynylphenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide from EXAMPLE 6 for phenylacetylene and 3- bromopyridine for N-isopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide, the title compound was obtained as a solid.

1H NMR (CDCl3) δ 0.66 (m, 2H), 0.85 (m, 2H), 2.97 (m, 1H), 7.28 (m, 1H), 7.43-7.48 (m, 2H), 7.57 (t, 1H), 7.62 (s, 1H), 7.70 (d, 1H), 7.79 (d, 1H), 8.55 (m, 1H), 8.70 (m, 1H), 8.75 (s, 1H), 8.79 (dd, 1H) , 9.01 (s, 1H), 9.74 (br, NH).

EXAMPLE 10

N-isopropyl-1-[3-(3-Mhydroxy-3-methylbut-1-ynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide

Following the procedure of Step 5 of EXAMPLE 1, but substituting 2-methyl-3-butyn-2-ol for phenylacetylene, the title compound was obtained as a white solid.

1HNMR (acetone-d6) δ 1.24 (d, 6H), 1.53 (s, 6H), 4.17 (m, 1H), 4.52 (s, 1H, OH), 7.58-7.65 (m, 4H), 7.68 (s, 1H), 8.72 (m, 1H), 8.77 (dd, 1H), 8.84 (s, 1H), 9.62 (br, NH).

EXAMPLE 11

N-cyclopropyl-1-[3-(3-hydroxy-3-methylbut-1-ynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide

After applying the procedure of EXAMPLE 10, but substituting N-cyclopropyl-1-(3-ethynylphenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamidase of EXAMPLE 6 for N-isopropyl-1-(3 -ethynylphenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide, the title compound was obtained as a white solid.

1H NMR (acetone-d6) δ 0.57 (m, 2H), 0.78 (m, 2H), 1.53 (s, 6H), 2.93 (m, 1H), 4.53 (s, 1H, OH), 7.58-7.65 (m, 4H), 7.67 (s, 1H), 8.72 (m, 1H), 8.76 (dd, 1H), 8.85 (s, 1H), 9.69 (br, NH).

EXAMPLE 12

N-isopropyl-1-[3-(1-hydroxycyclopentyl)ethynylphenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide

Following the procedure of Step 5 of EXAMPLE 1, but substituting 1-ethynylcyclopentanoate for phenylacetylene, the title compound was obtained as a white solid.

1H NMR (CDCl3) δ 1.28(d,6H), 1.76-1.80 (m, 2H), 1.84-1.88 (m, 3H), 1.98-2.06 (m, 4H), 4.27 (m, 1H), 7.36 (d, 1H), 7.44-7.50 (m, 3H), 7.56 (d, 1H), 8.68 (m, 1H), 8.79 (dd, 1H), 8.97 (s, 1H), 9.63 (br , NH).

EXAMPLE 13

N-isopropyl-[3-(1-hydroxycyclopropyl)ethynylphenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide

Step 1: 1-ethynylcyclopropanol.

1-ethynylcyclopropanol was prepared after applying the procedure described in J. Org.Chem. 1976,41, 1237 from [(1-ethoxycyclopropyl)oxy]trimethylsilane and ethynyl magnesium bromide, and obtained as a liquid.

Step 2: N-isopropyl-1-[3-(1-hydroxycyclopropylctynylphenyl]-1,4-dihydron.81-naphthyridin-4-one-3-carboxamide.

After applying the procedure from Step 5 of EXAMPLE 1, but substituting the product from Step 1 for phenylacetylene, N-isopropyl-1-[3-(1-hydroxycyclopropyl)ethynylphenyl]-1,4-dihydro[1,8]nafliridin-4-one The -3-carboxamide compound was obtained as a solid.

1H NMR CCDCl3) δ 1.09 (m, 2H), 1.17(m, 2H), 1.28 (d, 6H), 2.57(s, 1H, OH), 4.28 (m, 1H), 7.35 (d, 1H), 7.44 -7.50 (m, 3H), 7.54 (d, 1H), 8.68 (m, 1H), 8.79 (dd, 1H), 8.96 (s, 1H), 9.63 (br, NH).

EXAMPLE 14

N-isopropyl-1-{3-[4,4,4-trifluoro-3-hydroxy-3-(trifluoromethyl)but-1-ynyl]phenyl}-1,4-dihydro[1,8]naphthyridine-4- on-3-carboxamide

Step 1: 1,1,1-trifluoro-2-(trifluoromethyl)-4-(trimethylsilyl)but-3-yn-2-ol.

To a solution of trimethylsilylacetylene (4mL) in THF (30mL) at -78°C was added 2.5M n-butyllithium in hexanes (14mL) and the resulting mixture was stirred for 1 hour. Excess hexafluoroacetone was blown into the cold mixture, and stirring was continued for 4 hours. After warming to room temperature, the mixture was triturated with saturated aqueous ammonium chloride solution and partitioned between ether and water. The organic phase was dried and evaporated to give 1,1,1-Mfluoro-2-(trifluoromethyl)-4-(trimethylsilyl)but-3-yn-2-ol as a liquid.

Step 2: N-isopropyl-1-{3-[4,4,4-trifluoro-3-hydroxy-3-(trifluoromethyl)but-1-ynyl]phenyl}-1,4-dihydro[1,8]naphthyridine -4-one-3-carboxamide.

To a solution of 1,1,1-trifluoro-2-(trifluoromethyl)-4-(trimethylsilyl)but-3-yn-2-ol from Step 1 (6.8 mmol) in 10 mL of THF was added 1 M tetrabutylammonium fluoride (8.5 mL) and the resulting mixture was refluxed for 30 min to remove the TMS protecting group. The procedure of Step 5 of EXAMPLE 1 was then applied, but substituting this solution for phenylacetylene, to give N-isopropyl-1-{3-[4,4,4-trifluoro-3-hydroxy-3-(trifluoromethyl)but-1- inyl]phenyl}-1,4-dinidro[1,8]naphthyridin-4-one-3-carboxamide compound as a solid.

1H NMR (acetone-d6) δ 1.24 (d, 6H), 4.17 (m, 1H), 7.60 (m, 1H), 7.72-7.79 (m, 2H), 7.83 (d, 1H), 7.90 (s, 1H ), 8.14 (s, 1H, OH), 8.72 (m, 1H), 8.77 (dd, 1H), 8.85 (s, 1H), 9.62 (br, NH).

EXAMPLE 15

N-isopropyl-1-[3-(3-hydroxy-3-phenylbut-1-ynyl)phenyl]-1,4-dihydro[1,8]naphthyridim-4-one-3-carboxamide

A mixture of N-isopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide from Step 4 of EXAMPLE 1, 2-phenyl-3-butyn-2-ol ( 2 eq), triethylamine (1.66 eq), bis(diphenylphosphino)ferrocene]dichloropalladium(n) (0.05 eq), and copper(I) iodide (5mg/mmol) in DMF (20mL/mmol) was heated at 85°C for 18 hours. After cooling to room temperature, the resulting mixture was quenched with saturated aqueous ammonium chloride and partitioned between ethyl acetate and water. The crude product of the organic phase was chromatographed on silica gel, eluted with 20% ether in methylene chloride. The purified product was stirred in ether at room temperature for 3 hours and filtered to give the title compound as a white solid.

1H NMR(acetone-d6) δ 1.24 (d, 6H), 1.79 (s, 3H), 4.18 (m, 1H), 5.22 (s, 1H, OH), 7.26 (t, 1H), 7.35 (t, 2H )S 7.59 (m, 1H), 7.66 (m, 3H), 7.73 (d, 2H), 7.76 (s, 1H), 8.72 (m, 1H), 8.77 (dd, 1H), 8.84 (s, 1H) , 9.62 (no, NH).

EXAMPLE 16

N-cyclopropyl-1-[3-(1-oxido-3-pyridinylyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide

Step 1: 3-ethynylpyridine N-oxide.

To a solution of 3-ethynylpyridine in methylene chloride (5mL/mmol) at room temperature was added m-chloroperoxybenzoic acid (m-CPBA, 70% purity, 1.2 eq) and the resulting mixture was stirred for 2 hours. A further amount of m-CPBA was added (0.25 eq) and stirring was continued for 1 hour. Calcium hydroxide (2 eq) was added and after 15 minutes the mixture was filtered through celite and the filtrate was evaporated. The remaining solid was stirred in ether for 3 hours and filtered to give the 3-ethynylpyridine N-oxide compound as a white solid.

Step 2: N-cyclooropropyl-1-[3-(1-oxido-3-pyridinylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide.

After applying the procedure of EXAMPLE 15, but substituting N-cyclopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide from Step 1 of EXAMPLE 6 for N-isopropyl-1 -(3-bromophenyl)-1,4-dihydro[1,8]nafliridin-4-one-3-carboxamide, and 3-ethynylpyridine N-oxide from Step 1 for 2-phenyl-3-butyn-2-ol, The N-cyclopropyl-1-[3-(1-oxido-3-pyridinylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide compound was obtained as a white solid,

1H NMR (CDCl3) δ 0.66 (m, 2H), 0.84 (m, 2H), 2.96 (m, 1H), 7.26 (m, 1H), 7.37 (d, 1H), 7.45-7.48 (m, 2H) , 7.58-7.62 (m, 2H), 7.69 (d, 1H), 8.16 (d, 1H), 8.31 (s, 1H), 8.69 (m, 1H), 8.79 (dd, 1H), 8.99 (s, 1H ), 9.73 (no, NH).

EXAMPLE 17

N-isopropyl-1-[3-(3-amino-3-ethylpent-1-ynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide

Following the procedure of EXAMPLE 15, but substituting 2-phenyl-3-butyn-2-ol for 1,1-diethylpropargylamine, the title compound was obtained as a solid.

1HNMR (CDCl3) δ 1.05 (t, 6H), 1.28 (d, 6H), 1.57 (m, 2H), 1.69 (m, 2H), 4.27 (m, 1H), 7.33 (d, 1H), 7.44-7.49 (m, 3H), 7.53 (d, 1H), 8.69 (m, 1H), 8.79 (dd, 1H), 8.97 (s, 1H), 9.63 (br, NH). (NH2 was not observed).

EXAMPLE 18

N-cyclopropyl-1-[3-(3-amino-3-ethylpent-1-ynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide

After applying the procedure of EXAMPLE 17, but substituting N-cyclopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamidiz of Step 1 of EXAMPLE 6 for N-isopropyl-1- (3-Bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide, the title compound was obtained as a solid.

1H NMR (CDCl3) δ 0.66 (m, 2H), 0.84 (m, 2H), 1.05 (t, 6H), 1.57 (m, 2H), 1.70 (m, 2H), 2.96 (m, 1H), 7.33 ( d, 1H), 7.44-7.49 (m, 3H), 7.54 (d, 1H), 8.69 (m, 1H), 8.77 (dd, 1H), 8.97 (s, 1H), 9.75 (br, NH). (NH2 was not observed).

EXAMPLE 19

N-isopropyl-1-[3-(3-quinophenylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide

After applying the procedure of EXAMPLE 15, but substituting N-isopropyl-1-(3-ethynylphenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide from Step 2 of EXAMPLE 5 for 2-phenyl- 3-butyn-2-ol, and 3-bromoquinoline for N-isopropyl-1-(3-bromophenyl)-1-dihydro[1,8]naphthyridin-4-one-3-carboxamide, the title compound was obtained as a solid.

1H NMR (CDCl3) δ 1.32(d, 6H), 4.32(m, 1H), 7.48-7.51 (m, 2H), 7.58-7.65 (m, 2H), 7.71 (s, 1H), 7.73-7.80 (m , 2H), 7.83 (d, 1H), 8.12 (d, 1H), 8.35 (s, 1H), 8.75 (m, 1H), 8.85 (dd, 1H), 9.02 (s, 1H), 9.06 ( s, 1H), 9.65 (br, NH).

EXAMPLE 20

N-isopropyl-1-[3-(1-oxido-3-quinolinylethenyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide

Following the procedure of EXAMPLE 19, but substituting 3-bromoquinoline N-oxide for 3-bromoquinoline, the title compound was obtained as a solid.

1H NMR (CDCl3) δ 1.33 (d, 6H), 4.32 (m, 1H), 7.49-7.53 (m, 2H), 7.63 (t, 1H), 7.68-7.73 (m, 2H), 7.75-7.83 (m , 2H), 7.88-7.92 (m, 2H), 8.63 (s, 1H), 8.73-8.78 (m, 2H), 8.86 (dd, 1H), 9.05 (s, 1H), 9.67 (br, NH ).

EXAMPLE 21

N-isopropyl-1-[3-(cyclopropylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide

Following the procedure of EXAMPLE 15, but substituting cyclopropylacetylene (Tetrahedron letters 2000, 41,4007) for 2-phenyl-3-butyn-2-ol, the title compound was obtained as a gray solid.

1H NMR (CDCl3) δ 0.83 (m, 2H), 0.90 (m, 2H), 1.31 (d, 6H), 1.48 (m, 1H), 4.31 (m, 1H), 7.33 (m, 1H), 7.45- 7.51 (m, 3H), 7.55 (d, 1H), 8.72 (m, 1H), 8.83 (dd, 1H), 9.01 (s, 1H), 9.68 (br, NH).

EXAMPLE 22

N-isopropyl-1-[3-(6-amino-3-pyridinylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide

Following the procedure of EXAMPLE 19, but substituting 5-bromo-2-aminopyridine for 3-bromoquinoline, the title compound was obtained as a solid.

1H NMR (CDCl3) δ 1.33 (d, 6H), 4.31 (m, 1H), 4.71 (br, NH2), 6.49 (d, 1H), 7.40 (m, 1H), 7.48 (m, 1H), 7.54- 7.60 (m, 3H), 7.68 (d, 1H), 8.28 (s, 1H), 8.72 (m, 1H), 8.83 (dd, 1H), 9.04 (s, 1H), 9.67 (br, NH).

EXAMPLE 23

N-isopropyl-1-{3-[5-(1-hydroxy-1-methylethyl)-1-oxido-3-pyridinylethynyl]phenyl}-1,4-dihydro[1,8]naphthyridin-4-one-3 -carboxamide

Step 1: 3-bromo-5-(1-hydroxy-1-methylethyl)pyridine.

A 3M solution of methyl magnesium bromide in ether (4mL, 12mmol) was added to a solution of ethyl 5-bromonicotinate (1.02g, 4.4rαmol) in diethyl ether (15mL) at -30°C. The resulting mixture was refluxed for 2 hours, then cooled and quenched. with an excess of 0.5M aqueous monobasic sodium phosphate, and separated between ether and water. The organic phase product was chromatographed on silica gel, eluting with a 2:1:2 mixture of ether, pentane and ammonium-saturated methylene chloride, to give the compound 3-bromo-5-(1-hydroxy-1-methylethyl)pyridine as a yellow oil .

Step 2: 3-bromo-5-(1-hydroxy-1-methylethyl)pyridine-N-oxide.

To a solution of 3-bromo-5-(1-hydroxy-1-methylethyl)pyridine from Step 1 (3.1 mmol) in chlorophonic (10 mL) was added m-chloroperoxybenzoic acid 70% (1.5 eq) and the resulting mixture was stirred at room temperature during 18 hours. An excess of calcium hydroxide was added and after stirring for 5 minutes the mixture was filtered through celite and the filtrate was evaporated. The crude material was chromatographed on silica gel, eluting with 10% ethanol in methylene chloride (saturated with ammonium) to give the 3-bromo-5-(1-hydroxy-1-methylethyl)pyridine-N-oxide compound as a solid.

Step 3: N-isopropyl-1-{3-[5-(1-hydroxy-1-methylethyn-1-oxido-3-pyridinylethynyl]phenyl}-1,4-dihydro[1,8]naphthyridin-4-one -3-carboxamide.

After applying the procedure of EXAMPLE 15, but changing N-isopropyl-1-(3-ethynylphenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide from EXAMPLE 5 for 2-phenyl-3-butyne -2-ol, and 3-bromo-5-(1-hydroxy-1-methylethyl)pyridine-N-oxide from Step 2 for N-isopropyl-1(3-bromophenyl)-1,4-dihydro[1,8 ]naphthyridin-4-one-3-carboxamide, the compound N-isopropyl-1-{3-[5-(1-hydroxy-1-methylethyl)-1-oxido-3-pyridinylethynyl]phenyl}-1,4 -dihydro[1,8]naphthyridin-4-one-3-carboxamide as a solid.

1H NMR CDCl3) δ 1.32(d, 6H), 1.64 (s, 6H), 2.22 (br, 1H, OH), 4.30 (m, 1H), 7.45-7.52 (m, 2H), 7.60 (t, 1H) , 7.66 (s, 1H), 7.72 (d, 1H), 7.98 (s, 1H), 8.70 (br, 2H), 8.73 (m, 1H), 8.84 (dd, 1H), 9.03 (s, 1H), 9.68 (no, NH).

EXAMPLE 24

N-isopropyl-1-{3-[6-(1-hydroxy-1-methylethyl)-3-pyridinylethynyl]phenyl}-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide

Step 1: 5-bromo-2-(1-hydroxy-1-merylethynepyridine).

To a suspension of 2,5-dibromopyridine in toluene (12mL/mmol) cooled to -78°C was added n-butyllithium 2.5M in hexanes (1.05eq) and the resulting mixture was stirred in the cold for 2.5 hours. Acetone (2eq) was added and stirring was continued for 1.5 h. After quenching with saturated aqueous ammonium chloride, the mixture was warmed to room temperature and partitioned between ethyl acetate and water. The organic phase product was chromatographed on silica gel, eluting with 20% ethyl acetate in hexane, to give the compound 5-bromo-2-(1-hydroxy-1-methylethyl)pyridine as a syrup.

Step 2: 5-bromo-2-(1-methyl-1-{[2-(trimethylsilyl)ethoxy]methoxy}ethyl)pyridine.

N,N-diisopropylethylamine (37.3 mmol) and 2-(trimethylsilyl) were added to a solution of 5-bromo-2-(1-hydroxy-1-methylethyl) pyridine from Step 1 (14 mmol) in methylene chloride (50 mL) at 0°C. )ethoxymethyl chloride (15.3 mmol). The resulting mixture was stirred at room temperature for 18 hours, then refluxed for 24 hours. After cooling to room temperature, the mixture was quenched with saturated aqueous ammonium chloride and partitioned between methylene chloride and water. The crude product of the organic phase was chromatographed on silica gel, eluting with 6% ethyl acetate in hexane, to give the compound 5-bromo-2-(1-methyl-1-{[2-(trimethylsilyl)ethoxy]methoxy}ethyl)pyridine ,

Step 3: 2-(1-methyl-1-{[2-(trimethylsilyl)eoxy]methoxy}ethyl)-5-[(trimethylsilyl)ethynyl]pyridine.

After applying the procedure from Step 5 of EXAMPLE 1, but substituting the product from Step 2 for N-isopropyl-1-(3-bromophenyl])-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide and trimethylsilylacetylene for phenylacetylene, the compound 2-(1-methyl-1-{[2-(trimethylsilyl)ethoxy]methoxy}ethyl)-5-[(trimethylsilyl)ethynyl]pyridine was obtained.

Step 4: 5-ethynyl-2-(1-methyl-1-{[2-(trimethylsilyl)ethoxy]methoxy}ethyl)pyridine.

After applying the procedure from Step 2 of EXAMPLE 5, but substituting the product from Step 3 for N-isopropyl-1-[3-(trimethylsilylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide , the compound 5-ethynyl-2-(1-methyl-1-{[2-(trimethylsilyl)ethoxy]methoxy}ethyl)pyridine was obtained.

Step 5: N-isopropyl-1-(3-{[6-(1-methyl-1-{{2-trimethylsilyl)ethoxy]methoxy}ethyl)pyridin-3-yl]ethynyl}phenyl)-1,4- dihydro[1,8]naphthyridin-4-one-3-carboxamide.

After applying the procedure from Step 5 of EXAMPLE 1, but changing the product from Step 4 for phenylacetylene, the compound N-isopropyl-1-(3-{[6-(1-methyl-1-{{2-trimethylsilyl)ethoxy]methoxy) was obtained }ethyl)pyridin-3-yl]ethynyl}phenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide.

Step 6: N-isopropyl-1-(3-[6-(1-hydroxy-1-methylethyl)-3-pyridinylethyl}phenyl}-1,4-dihydro[1,8]naphthyridin-4-one-3- carboxainide.

In solution N-isopropyl-1-(3-{[6-(1-methyl-1-{{2-trimethylsilyl)ethoxy]methoxy}ethyl)pyridin-3-yl]ethynyl}phenyl)-1,4-dihydro Trifluoroacetic acid (3.2 mL/mmol) was added to the [1,8]naphthyridin-4-one-3-carboxamide product from Step 5 in methylene chloride (32 mL/mmol) at 0°C. The resulting mixture was stirred at 0°C for 2 hours and then at room temperature for 2 hours. The mixture was neutralized slowly with saturated aqueous sodium bicarbonate and partitioned between methylene chloride and water. The crude material of the organic phase was chromatographed on silica gel eluted with 40% ether in methylene chloride and the purified product was stirred in ether at room temperature for 2 hours and filtered to give N-isopropyl-1-{3-[6-(1-hydroxy -1-methylethyl)-3-pyridinylethynyl]phenyl}-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide compound as a solid.

1H NMR (acetone-d6) δ 1.24 (d, 6H), 1.50 (s, 6H), 4.18 (m, 1H), 4.57 (s, 1H, OH), 7.61 (m, 1H), 7.69-7.74 (m , 3H), 7.78 (m, 1H), 7.88 (s, 1H), 7.93 (dd, 1H), 8.68 (s, 1H), 8.74 (m, 1H), 8.78 (dd, 1H), 8.88 (s, 1H), 9.63 (br, NH).

EXAMPLE 25

N-isopropyl-1-{3-[6-(1-hydroxy-1-methylethyl)-1-oxido-3-pyridinylethynyl]phenyl}-1,4-dihydro[1,8]naphthyridin-4-one-3 -carboxamide

After applying the procedure from Step 2 of EXAMPLE 23, but changing N-isopropyl-1-{3-[6-(1-hydroxy-1-methylethyl)-3-pyridinylethynyl]phenyl]}-1,4-dihydro[1,8 ]nafliridin-4-one-3-carboxamide from EXAMPLE 24 for 3-bromo-5-(1-hydroxy-1-methylethyl)pyridm, the title compound was obtained as a solid.

1H NMR (acetone-d6) δ 1.25 (d, 6H), 1.60 (s, 6H), 4.18 (m, 1H), 7.24 (s, 1H, OH), 7.60-7.63 (m, 3H), 7.72-7.78 (m, 2H), 7.82 (d, 1H), 7.91 (s, 1H), 8.46 (s, 1H), 8.74 (m, 1H), 8.78 (dd, 1H), 8.87 (s, 1H), 9.62 ( no, NH).

EXAMPLE 26

N-isopropyl-1-{3-[4-(1-hydroxy-1-methylethyl)-2-pyridinylethynyl]phenyl}-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide

Step 1: methy]2-bromoisonicotinate.

To a solution of 2-bromoisonicotinic acid (Chem. Pharm. Buli. 1990, 38, 2446) (2.0g) in tetrahydrofuran (100mL) was added an excess of ethereal diazomethane and the resulting mixture was stirred at room temperature for 1 hour. The mixture was evaporated and the product chromatographed on silica gel, eluted with a 1:3 mixture of ethyl acetate and hexane, to give methyl 2-bromoisonicotinate ester as a colorless liquid.

Step 2: 2-bromo-4-(1-hydroxy-1-methylethynpyridine).

After applying the procedure from Step 1 of EXAMPLE 23, but changing methyl 2-bromoisonicotinate from Step 1 for ethyl 5-bromonicotinate, the compound 2-bromo-4-(1-hydroxy-1-methylethyl)pyridine was obtained as a white solid.

Step 3: N-isopropyl-1-{3-[4-(1-hydroxy-1-methylethyl)-2-pyridinylethynyl]phenyl}-1,4-dihydro[1,8]naphthyridin-4-one-3- carboxamide.

After applying the procedure of EXAMPLE 19, but substituting 2-bromo-4-(1-hydroxy-1-methylethyl)pyridine from Step 2 for 3-bromoquinoline, the compound N-isopropyl-1-{3-[4-(1- hydroxy-1-methylethyl)-2-pyridinylethynyl]phenyl}-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide as a yellow foam.

1H NMR (acetone-d6) δ l .27 (d, 6H), 1.55 (s, 6H), 4.20 (m, 1H), 4.42 (s, 1H, OH), 7.52 (m, 1H), 7.63 ( m, 1H), 7.72-7.79 (m, 3H), 7.84 (d, 1H), 7.95 (s, 1H), 8.55 (d, 1H), 8.77 (m, 1H), 8.80 (dd, 1H), 8.92 (s, 1H), 9.65 (br, NH).

EXAMPLE 27

N-isopropyl-1-{3-[5-(1-hydroxy-1-methylethyl)-2-pyridinylethynyl]phenyl}-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide

Step 1: 2-bromo-5-(1-hydroxy-1-methylethyl)pyridine.

A solution of 2,5-dibromopyridine in diethyl ether (5mL/mmol) was cooled to -78°C, and n-butyllithium 2.5M in hexanes (1.05 eq) was slowly added. After 2 hours in the cold, acetone (1.3 eq) was added and stirring was continued for 1 hour. The resulting mixture was quenched with saturated aqueous ammonium chloride solution, warmed to room temperature, and partitioned between ether and water. The crude product of the organic phase was triturated with 1:1 ether-hexane and filtered to give the compound 2-bromo-5-(1-hydroxy-1-methylethyl)pyridine as a solid.

Step 2: 5-(1-hydroxy-1-methylethyl)-2-[(trimethylsilyl)ethynyl]pyridine.

After applying the procedure from EXAMPLE 15, but changing the product 2-bromo-5-(1-hydroxy-1-methylethyl)pyridine from Step 1 for N-isopropyl-1-(3-bromophenyl)-1,4-dihydro[1, 8]naphthyridin-4-one-3-carboxamide and trimethylsilylacetylene for 2-phenyl-3-butyn-2-ol, the compound 5-(1-hydroxy-1-methylethyl)-2-[(trimethylsilyl)ethynyl]pyridine was obtained .

Step 3: 2-ethynyl-5-(1-hydroxy-1-methylethyl)pyridine.

After applying the procedure from Step 2 of EXAMPLE 5, but changing the product 5-(1-hydroxy-1-methylethyl)-2-[(trimethylsilyl)ethynyl]pyridine from Step 2 for N-isopropyl-1-[3-(trimethylsilylethynyl)phenyl ]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide, the compound 2-ethynyl-5-(1-hydroxy-1-methylethyl)pyridine was obtained.

Step 4: N-isopropyl-1-{3-[5-(1-hydroxy-1-methylethyl)-2-pyridinylethynyl]phenyl}-1,4-dihydro[1.8]naphthyridin-4-one-3-carboxamide.

After applying the procedure from EXAMPLE 15 but changing the product 2-ethynyl-5-(1-hydroxy-1-methylethyl)pyridine from Step 3 for 2-phent-3-butyn-2-ol, the compound N-isopropyl-1- {3-[5-(1-Hydroxy-1-methylethyl)-2-pyridinylethynyl]phenyl}-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide.

1H NMR (CDCl3) δ l .32 (d, 6H), 1.66 (s, 6H), 2.08 (s, l H, OH), 4.31 (m, 1H), 7.46-7.55 (m, 3H), 7.61 ( t, 1H), 7.71 (s, 1H), 7.78 (d, 1H), 7.86 (dd, 1H), 8.73 (m, 1H), 8.77 (m, 1H), 8.83 (dd, 1H), 9.04 (s , 1H), 9.67 (br, NH).

EXAMPLE 28

N-isopropyl-1-{3-[6-(1-hydroxy-1-methylethyl)-2-pyridinylmethyl]phenyl}-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide

Step 1: 2-bromo-6-(1-hydroxy-1-methyl]ethyl)pyridine.

After applying the procedure from Step 1 of EXAMPLE 27, but replacing 2,6-dibromopyridine with 2,5-dibromopyridine, the compound 2-bromo-6-(1-hydroxy-1-methylethyl)pyridine was obtained as a solid.

Step 2: N-isopropyl-1-{3-[6-(1-hydroxy-1-methylethyl)-2-pyridinylethynyl]phenyl}-1,4-dihydro[1,8]naphthyridin-4-one-3- carboxamide.

After applying the procedure from EXAMPLE 19, but changing the product 2-bromo-6-(1-hydroxy-1-methylethyl)pyridine from Step 1 for 3-bromoquinoline, obtaining the compound N-isopropyl-1-{3-[6-(1 -hydroxy-1-methylethyl)-2-pyridinylethynyl]phenyl}-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide.

1H NMR (CDCl3) δ l .31 (d, 6H), l .58 (s, 6H), 4.32 (m, 1H), 4.83 (s, 1H, OH), 7.38 (d, 1H), 7.43-7.52 (m, 3H), 7.60 (t, 1H), 7.70-7.75 (m, 2H), 7.79 (d, 1H), 8.74 (m, 1H), 8.84 (dd, 1H), 9.03 (s, 1H), 9.66 (no, NH).

EXAMPLE 29

N-cyclopropyl-1-{3-[6-(1-hydroxy-1-methylethyl)-1-oxido-3-pyridinylethynyl]phenyl}-1,4-dihydro[1,8]naphthyridin-4-one-3 -carboxamide

Step 1: 5-bromo-2-(1-hydroxy-1-methylethynpyridineN-oxide).

After applying the procedure from Step 2 of EXAMPLE 23, but substituting 5-bromo-2-(1-hydroxy-1-methylethyl)pyridine from Step 1 of EXAMPLE 24 for 3-bromo-5-(1-hydroxy-1-methylethyl)pyridine, the compound 5-bromo-2-(1-hydroxy-1-methylethyl)pyridine N-oxide was obtained.

Step 2: N-cyclopropyl-1-{3-[6-(1-hydroxy-1-methylethyl)-1-oxido-3-pyridinylethynyl]phenyl}-1,4-dihydro[1,8]naphthyridine-4- on-3-carboxamide.

After applying the procedure of EXAMPLE 15, but changing N-cyclopropyl-1-(3-ethynylphenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide from EXAMPLE 6 for 2-phenyl-3-butyne -2-ol and 5-bromo-2-(1-hydroxy-1-methylethyl)pyridine-N-oxide from Step 1 for N-isopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8 ]naphthyridin-4-one-3-carboxamide, the compound N-cyclopropyl-1-{3-[6-(1-hydroxy-1-methylethyl)-1-oxido-3-pyridinylethynyl]phenyl}-1,4 -dihydro[1,8]naphthyridin-4-one-3-carboxamide solid.

1H NMR (CDCl3) δ 0.66 (m, 2H), 0.84 (m, 2H), 1.66 (s, 6H), 2.96 (m, 1H), 7.34 (d, 1H), 7.43-7.50 (m, 4H ), 7.58-7.62 (m, 2H), 7.69 (d, 1H), 8.33 (s, 1H, OH), 8.69 (m, 1H), 8.79 (dd, 1H), 8.99 (s, 1H), 9.73 ( no, NH).

EXAMPLE 30

N-isopropyl-1-{3-[(4-pyridin-3-ylphenyl)ethynyl]phenyl}-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide

Step 1: 3-(4-bromophenyl)pyridine.

A mixture of pyridine-3-boronic acid, 1,3-propanediol cyclic ester, 4-bromoiodobenzene (1.1 eq), [1,1'-bis(diphenylphosphino)ferrocene]dic]oropalladium(II) (0.05 eq) and 2M aqueous sodium of carbonate (5 eq) in N,N-dimethylformamide (2mL/mmol) was stirred at 85°C for 4 hours. After quenching with a saturated aqueous solution of ammonium chloride, the mixture was partitioned between ethyl acetate and water, and the crude product of the organic phase was chromatographed on silica gel, eluted with a 1:9 mixture of ethyl acetate and hexane to obtain the 3-(4-bromophenyl)pyridine compound as a solid.

Step 2: N-isopropyl-1-{3-[(4-pyridin-3-ylphenyl)ethynyl]phenyl}-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide.

After applying the procedure of EXAMPLE 19, but changing the product from Step 1 for 3-bromoquinoline, the compound N-isopropyl-1-{3-[(4-pyridin-3-ylphenyl)ethynyl]phenyl}-1,4-dihydro[ 1,8]naphthyridin-4-one-3-carboxamide.

1HNMR (CDCl3) δ 1.28 (d, 6H), 4.28 (m, 1H), 7.38 (m, 1H), 7.42 (d, 1H), 7.48 (m, 1H), 7.53-7.64 (m, 6H) , 7.70 (d, 1H), 7.88 (d, 1H), 8.60 (m, 1H), 8.71 (m, 1H), 8.82 (dd, 1H), 8.86 (s, 1H), 9.02 (s, 1H), 9.63 (no, NH).

EXAMPLE 31

N-isopropyl-1-(3-{[5-(1-hydroxy-1-methylethyl)thien-2-yl]ethynyl}phenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3 -carboxamide

Step 1: 2-bromo-5-(1-hydroxy-1-methylethyl)thiophene.

To a solution of 2-acetyl-5-bromothiophene in THF (2.5mL/mmol) at -30°C was added 1.4M methylmagnesium bromide 3:1 toluene-THF (1.5 eq) and the resulting mixture was warmed to -10°C and stirred for 1.5 hours. After quenching with saturated aqueous ammonium chloride, the mixture was partitioned between ether and water. The organic fraction was dried and evaporated, and the crude material was chromatographed on silica gel, eluting with a t:4 mixture of ether and hexane, to give the 2-bromo-5-(1-hydroxy-1-methylethyl)thiophene compound.

Step 2: 2-(1-hydroxy-1-methylethyl)-5-trimethylsilylethynyl thiophene.

After applying the procedure from EXAMPLE 15, but changing the product from Step 1 for N-isopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide and trimethylsilylacetylene for 2-phenyl -3-butyn-2-ol, 2-(1-hydroxy-1-methylethyl)-5-trimethylsilylethynyl thiophene compound was obtained.

Step 3: 2-ethynyl-5-(1-hydroxy-1-methylethyl)thiophene.

After applying the procedure from Step 2 of EXAMPLE 5, but substituting the product from Step 2 for N-isopropyl-1-[3-(trimethylsilylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide , 2-ethynyl-5-(1-hydroxy-1-methylethyl)thiophene compound was obtained.

Step 4: N-isopropyl-1-(3-{[5-(1-hydroxy-1-methylethyl)thien-2-yl]ethynyl}phenin-1,4-dihydro[1,8]naphthyridin-4-one -3-carboxamide.

After applying the procedure of EXAMPLE 15, but changing the 2-ethynyl-5-(1-hydroxy-1-methylethyl)thiophene product from Step 3 for 2-phenyl-3-butyn-2-ol, N-isopropyl-1-(3- The {[5-(1-hydroxy-1-methylethyl)thien-2-yl]ethynyl}phenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide compound was obtained as a solid.

1H NMR CDCl3) δ 1.31 (d, 6H), 1.70 (s, 6H), 2.42 (s, 1H, OH), 4.31 (m, 1H), 6.87 (d, 1H), 7.16 (d, 1H), 7.42 (d, 1H), 7.48 (m, 1H), 7.59 (t, 1H), 7.63 (s, 1H), 7.68 (d, 1H), 8.73 (m, 1H), 8.84 (dd, 1H), 9.02 ( s, 1H), 9.68 (br, NH).

EXAMPLE 32

N-isopropyl-1-(3-{[2-(1-hydroxy-1-methylethyl)-1,3-thiazol-5-yl]ctynyl}phenyl)-1,4-dihydro[1,8]naphthyridine- 4-one-3-carboxamide

Step 1: 2-(1-hydroxy-1-methylethyl) thiazole.

To a solution of thiazole in ether (1mL/mmol) at -78°C was added 2.2M n-butyllithium in hexanes (1.1 eq) and the resulting mixture was stirred for 30 minutes. Acetone (1.2 eq) was added and the mixture was stirred at -78°C for a further 30 minutes. The mixture was quenched in cold saturated aqueous ammonium chloride and warmed to room temperature, then partitioned between ether and water. The organic phase was dried and evaporated to give the crude product as an orange-brown oil, which was used as such in the next step.

Step 2: 2-(1-methyl-1-{[2-(trimethylsilyl)ethoxy]methoxy}ethyl)thiazole.

After applying the procedure from Step 2 of EXAMPLE 24, but substituting the product from Step 1 for 5-bromo-2-(1-hydroxy-1-methylethyl)pyridine, 2-(1-methyl-1-{[2-(trimethylsilyl)ethoxy The ]methoxy}ethyl)thiazole compound was obtained as an oil.

Step 3: 5-bromo-2-(1-hydroxy-1-methylethyl)thiazole.

Bromine (2 molar eq) was added to a solution of 2-(1-methyl-1-{[2-(trimethylsilyl)ethoxy]methoxy}ethyl)thiazole from Step 2 in chloroform (2mL/mmol) at room temperature and the resulting mixture was stirred for 1 hour. Solid sodium bicarbonate (0.55 eq) was added and the mixture was stirred for the next 5 hours. More sodium bicarbonate (0.55 eq) was added and stirring was continued for 18 hours. After the final addition of sodium bicarbonate, (0.55 eq) the mixture was stirred for 5 hours, diluted with chloroform, and the organic phase was washed with saturated aqueous sodium bicarbonate, then with water, dried and evaporated. The crude material was chromatographed, eluted with a 3:7 mixture of ethyl acetate and hexane, to give the desired product.

Step 4: N-isopropyl-1-(3-{[2-(1-hydroxy-1-methylethyn-1,3-thiazol-5-yl]ethynyl}phenyl)-1,4-dihydro[1,8] naphthyridin-4-one-3-carboxamide.

After applying the procedure of EXAMPLE 19, but changing the product from Step 3 for 3-bromoquinoline, the compound N-isopropyl-1-(3-{[2-(1-hydroxy-1-methylethyl)-1,3-thiazol- 5-yl]ethynyl}phenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide as a solid.

1H NMR CDCl3) δ 1.29(d,6H), 1.68 (s, 6H), 2.90 (s, 1H, OH), 4.28 (m, 1H), 7.42 (d, 1H), 7.46 (m, 1H), 7.54 -7.60 (m, 2H), 7.66 (d, 1H), 7.82 (s, 1H), 8.70 (m, 1H), 8.80 (dd, 1H), 8.99 (s, 1H), 9.63 (br, NH).

EXAMPLE 33

1-[3-(1-oxido-3-pyridinylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide

Step 1: 1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide.

After applying the procedure from Step 4 of EXAMPLE 1, but substituting 28% aqueous ammonium hydroxide for isopropylamine, the compound 1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide was obtained as solid.

Step 2: 1-[3-(trimethylsilylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide.

After applying the procedure from Step 5 of EXAMPLE 1, but substituting 1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide from Step 1 for N-isopropyl-1-(3 -bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamides trimethylsilylacetylene for phenylacetylene, 1-[3-(trimethylsilylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridine- The 4-one-3-carboxamide product was obtained as a solid.

Step 3: 1-(3-ethynylphenine-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide).

1M tetrabutylammonium was added to a solution of 1-[3-(trimethylsilylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide from Step 2 in THF (30mL/mmol) at 0°C fluoride in THF (1.5 eq) and the resulting mixture was stirred at 0°C for 30 min. The mixture was partitioned between methylene chloride and water, and the organic phase was dried and evaporated. The crude 1-(3-ethynylphenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide product was used as such in the next step.

Step 4: 1-[3-(1-Oxido-3-pyridinylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide.

After applying the procedure of EXAMPLE 19, but substituting 1-(3-ethynylphenyl)-1,4-dihydro[1,8]nafliridin-4-one-3-carboxamide from Step 3 for N-isopropyl-1-(3-ethynylphenyl) -1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide and 3-bromopyridine N-oxide for 3-bromoquinoline, 1-[3-(1-oxido-3-pyridinylmethyl)phenyl] -1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide as a white solid.

1H NMR CDCl3) δ 5.84 (br, 1H,NH), 7.30 (m, 1H), 7.41 (d, 1H), 7.53 (m, 2H), 7.64 (t, 1H), 7.67 (s, 1H), 7.74 (d, 1H), 8.21 (d, 1H), 8.35 (s, 1H), 8.75 (m, 1H), 8.88 (dd, 1H), 9.05 (s, 1H), 9.52 (br, 1H, NH).

EXAMPLE 34

1-[3-(1-oxido-3-pyridinylethyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxylic acid

Step 1: Ethyl 1-[3-ethynylphenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxylate.

Following the procedures from Steps 1 and 2 of EXAMPLE 5, but substituting ethyl 1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxylate from Step 2 of EXAMPLE 1 for N-isopropyl- 1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide as starting material, ethyl 1-(3-ethynylphenyl)-1,4-dihydro[1,8] the naphthyridin-4-one-3-carboxylate compound was obtained as a solid.

Step 2: Ethyl 1-[3-(1-oxido-3-pyridinylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxylate.

After applying the procedure from EXAMPLE 15, but substituting ethyl 1-(3-ethynylphenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxylate from Step 1 for 2-phenyl-3-butyn-2 -ol and 3-bromopyridine N-oxide for N-isopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide, ethyl 1-[3-(1 -oxido-3-pyridinylethynyl)phenyl]-1,4-dihydro[1,8]nafliridin-4-one-3-carboxylate was obtained as a solid.

Step 3: 1-[3-(1-Oxido-3-pyridinylethyninephenine-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxylic acid).

After applying the procedure from Step 3 of EXAMPLE 1, but changing the ethyl 1-[3-(1-oxido-3-pyridinylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxylate ester from of Step 2 for Ethyl 1-(3-bromophenyl)-1,4-dihydro[1,8]naphthtridin-4-one-3-carboxylate, 1-[3-(1-oxido-3-pyridinylethynyl)phenyl]-1 ,4-dihydro[1,8]naphthyridin-4-one-3-carboxylic acid was obtained as a white solid.

1H NMR (DMSO-d6) δ 7.46 (t, 1H), 7.51 (d, 1H), 7.70 (t, 1H), 7.75 (m, 2H), 7.80 (d, 1H), 7.92 (s, 1H), 8.26 (d, 1H), 8.47 (s, 1H), 8.81 (dd, 1H), 8.89 (m, 1H), 8.97 (s, 1H).

Other variations or modifications, which will be apparent to those skilled in the art, are included within the scope and spirit of this invention. This invention is not limited except as set forth in the following claims.

Claims (33)

1. Compound represented by formula (I): [image] or pharmaceutically acceptable salts thereof, characterized in that R is H, -C1-6alkyl or -C3-6cycloalkyl; R 1 is H, or -C 1-6 alkyl, -C 3-6 cycloalkyl, -C 1-6 alkoxy, -C 2-6 alkenyl, -C 3-6 alkynyl, -C(O)-C 1-6 alkyl, -C(O)-aryl, -( C0-6alkyl)-SOn-C1-6alkyl), -(C0-6alkyl)-SOn-(aryl), phenyl, heteroaryl, or heterocycloC3-7alkyl group, where any of the groups is optionally substituted with 1-3 independent -C1 -6alkyl, -C1-6alkyl, OH, -N(C0-6alkyl)(C0-6alkyl), -(C0-6alkyl)-SOn-(C1-6alkyl), nitro, CN, =N-O-C1-6alkyl, - O-N=C1-6 alkyl, or halogen of the substituent; R 2 is absent, H, halogen, -C 1-6 alkyl, -C 3-6 cycloalkyl, -C 1-6 alkyl(C 3-6 cycloalkyl)(C 3-6 cycloalkyl), -C 1-6 alkoxy, phenyl, heteroaryl, heterocycloC 3-7 alkyl, nitro, CN, =N-O-C1-6alkyl, -O-N=C1-6alkyl, -N(C0-6alkyl)(C0-6alkyl), -NHSOn-(C1-6alkyl), -NHC(O)-C1-6alkyl, -NHC(O )-aryl, -C(O)-C1-6alkyl, -C(O)-O-C1-6alkyl, -C1-6alkyl(-N-OH), -C(N=NOH)C1-6alkyl, -C0 -6alkyl(oxy)C1-6alkyl-phenyl, -SOnNH(C0-6alkyl), or -(C0-6alkyl)-SOn-(C1-6alkyl), where phenyl, heteroaryl or heterocycloC3-7alkyl is optionally substituted with halogen, - C 1-6 alkyl, -C 1-6 alkoxy, hydroxy, -N(C 0-6 alkyl)(C 0-6 alkyl), or -C(O)-O-C 1-6 alkyl, and each alkyl is optionally substituted with 1-6 independent halogen or -OH of the substituent; n is 0, 1, or 2; R3 is absent, H, OH, -N(C0-6alkyl)(C0-6alkyl), halogen or C1-6alkyl, where each alkyl is optionally substituted with 1-6 independent halogens, OH, or -N(C0-6alkyl) (C0-6alkyl) substituent; R 4 , R 5 , R 6 , and R 7 are each independently H, halogen, -C 1-6 alkyl, -C 1-6 alkoxy, -SOn-(C 1-6 alkyl), nitro, CN, or -N(C 0-6 alkyl)(C 0-6 alkyl ), and every one is alki! optionally substituted with 1-6 independent halogen or -OH substituents; and R 8 is phenyl, pyridyl, pyrimidyl, indolyl, quinolinyl, thienyl, pyridonyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, or imidazolyl; or their oxides when R 8 is heteroaryl; or H, -C1-6alkyl, or -C3-6cycloalkyl, and each alkyl is optionally substituted with 1-6 independent halogens, -N(C0-6alkyl)(C0-6alkyl), -N(C3-7cycloalkyl)(C0- 6alkyl), -N(C3-7cycloalkyl)(C3-7cycloalkyl), N-heterocycloC4-7alkyl, -SOn-(C1-6alkyl), -SOn-(aryl), or -OH substituents. 2. The compound according to claim 1, or its pharmaceutically acceptable salts, characterized in that they are R2 and R3 absent; and R8 is H. 3. The compound according to claim 1, or its pharmaceutically acceptable salts, characterized in that R 8 is phenyl, pyridyl, pyrimidyl, indolyl, quinolinyl, thienyl, pyridonyl, oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, or imidazolyl; or its oxide, when R 8 is heteroaryl. 4. The compound according to claim 3, or its pharmaceutically acceptable salts, characterized in that R8 is phenyl. 5. The compound according to claim 3, or its pharmaceutically acceptable salts, characterized in that R8 is pyridyl, or its oxide. 6. The compound according to claim 3, or its pharmaceutically acceptable salts, characterized in that R8 is quinolinyl, or its oxide. 7. The compound according to claim 3, or its pharmaceutically acceptable salts, characterized in that R8 is thienyl, or its oxide. 8. The compound according to claim 3, or its pharmaceutically acceptable salts, characterized in that R8 is thiazolyl, or its oxide. 9. The compound according to claim 1, or its pharmaceutically acceptable salts, characterized in that R8 is -C3-6cycloalkyl, optionally substituted with 1-6 independent halogen, -N(C0-6alkyl)(C0-6alkyl), -N(C3-7cycloalkyl)(C0-6alkyl), -N(C3-7cycloalkyl)( C3-7cycloalkyl), N-heterocyclo4-7alkyl, -SOn-(C1-6alkyl), -SOn-(aryl), or -OH substituent. 10. The compound according to claim 1, or its pharmaceutically acceptable salts, characterized in that R8 is -C1-6alkyl, optionally substituted with 1-6 independent halogens, -N(C0-6alkyl)(C0-6alkyl), -N(C3-7cycloalkyl)(C0-6alkyl), -N(C3-7cycloalkyl)( C3-7cycloalkyl), N-heterocycloC4-7alkyl, -SOn-(C1-6alkyl), -SOn-(aryl), or –OH substituent. 11. Compound according to claim 1, characterized in that it consists of N-isopropyl-1-(3-ethynylphenyl)-1?4-dihydro[1,8]naphthyridin-4-one-3-carboxamide; or N-cyclopropyl-1-(3-ethynylphenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide; or pharmaceutically acceptable salts thereof. 12. Compound according to claim 1, characterized in that it consists of N-isopropyl-1-[3-(phenylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide; or N-isopropyl-1-{3-[(4-pyridin-3-ylphenyl)ethynyl]phenyl}-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide; or pharmaceutically acceptable salts thereof. 13. Compound according to claim 1, characterized in that it consists of N-isopropyl-1-[3-(2-pyridinylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide; N-isopropyl-1-[3-(4-pyridinylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide; N-isopropyl-1-[3-(1-oxido-4-pyridinylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide; N-isopropyl-1-[3-(3-pyridinylethynyl)phenyl]-1-dihydro[1,8]naphthyridin-4-one-3-carboxamide; N-isopropyl-1-[3-(1-oxido-3-ptridinylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxainide; N-cyclopropyl-1-[3-(3-pyridinylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide; N-cyclopropyl-1-[3-(1-oxido-3-pyridinylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide; N-isopropyl-1-[3-(6-amino-3-pyridinylethynyl)phenyl]-1,4-dihydro[1,8]nafliridin-4-one-3-carboxamide; N-isopropyl-1-{3-[5-(1-hydroxy-1-methylethyl)-1-oxido-3-pyridinylethynyl]phenyl}-1,4-dihydro[1,8]naphthyridin-4-one-3 -carboxamide; N-isopropyl-1-{3-[6-(1-hydroxy-1-methylethyl)-3-pyridinylethyl]phenyl}-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide; N-Isopropyl-1-(3-[6-(1-Hydroxy-1-methylethyl)-1-oxido-3-pyridinylethynyl-phenyl-1-dihydro-1-naphthyridin-one-S-carboxamide; N-Isopropyl-1-{3-[4-(1-Mhydroxy-1-methylethyl)-2-pyridinylethynyl-3-phenyl}-1H-dihydrotyl]Naphliridin-1-one-S-carboxamide; N-isopropyl-1-{3-[5-(1-hydroxy-1-methylethyl)-2-pyridinylethynyl]phenyl}-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide; N-isopropyl-1-{3-[6-(1-hydroxy-1-methylethyl)-2-pyridinylethynyl]phenyl}-1,4-dihydro[1,S]naphthyridin-4-one-3-carboxamide; N-cyclopropyl-1-{3-[6-(1-hydroxy-1-methylethyl)-1-oxido-3-pyridinylethynyl]phenyl}-1,4-dihydro[1,8]naphthyridin-4-one-3 -carboxamide; 1-[3-(1-oxido-3-pyridinylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide; or 1-[3-(1-oxido-3-pyridylethyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxylic acid; or pharmaceutically acceptable salts thereof. 14. Compound according to claim 1, characterized in that it consists of N-isopropyl-1-[3-(3-quinolinylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide; or N-isopropyl-1-[3-(1-oxido-3-quinolinylethenyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide; or pharmaceutically acceptable salts thereof. 15. Compound according to claim 1, characterized in that it consists of N-isopropyl-1-(3-{[5-(1-hydroxy-1-methylethyl)thien-2-yl]ethynyl}phenyl)-1,4-dihydro[1,8]naffyridin-4-one-3 -carboxamide; or pharmaceutically acceptable salts thereof. 16. Compound according to claim 1, characterized in that it consists of N-isopropyl-1-(3-{[2-(1-hydroxy-1-methylethyl)-1,3-thiazol-5-yl]ethynyl}phenyl)-1,4-dihydro[1,8]naphthyridine- 4-one-3-carboxamide; or pharmaceutically acceptable salts thereof. 17. Compound according to claim 1, characterized in that it consists of N-isopropyl-1-[3-(1-hydroxycyclopentyl)ethynylphenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide; N-isopropyl-1-[3-(1-hydroxycyclopropyl)ethynylphenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide; or N-isopropyl-1-[3-(cyclopropylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide; or pharmaceutically acceptable salts thereof. 18. Compound according to claim 1, characterized in that it consists of N-isopropyl-1-[3-(3-hydroxy-3-methylbut-1-ynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide; N-cyclopropyl-1-[3-(3-hydroxy-3-methylbut-1-ynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide; N-isopropyl-1-{3-[4,4,4-trifluoro-3-hydroxy-3-(trifluoromethyl)but-1-ynyl]phenyl}-1,4-dihydro[1,8]naphthyridine-4- on-3-carboxamide; N-isopropyl-1-[3-(3-hydroxy-3-phenylbut-1-ynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide; N-isopropyl-1-[3-(3-amino-3-ethylpent-1-ynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide; or N-cyclopropyl-1-[3-(3-amino-3-ethylpent-1-ynyl)phenyl]]-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide; or pharmaceutically acceptable salts thereof. 19. Pharmaceutical preparation, characterized in that it consists of a therapeutically effective amount of the compound according to claim 1, or its pharmaceutically acceptable salt; and a pharmaceutically acceptable carrier. 20. Pharmaceutical preparation according to claim 19, characterized in that it further contains leukotriene receptor antagonists, leukotriene biosynthesis inhibitors, M2/M3 antagonists, corticosteroids, H1 receptor antagonists or beta 2 adrenoceptor agonists. 21. Pharmaceutical preparation according to claim 19, characterized in that it further contains COKS-2 selective inhibitors, a statin, or an NSAID. 22. Method of treatment or prevention of asthma; chronic bronchitis; chronic obstructive pulmonary diseases; respiratory disorder syndrome in adults; respiratory disorder syndrome in children; coughing; chronic obstructive pulmonary diseases in animals; respiratory disorder syndrome in adults; ulcerative colitis; Crohn's disease; hypersecretion of gastric acid; bacterial, fungal or viral-induced sepsis or septic shock; endotoxic shock; laminitis or colic in horses; spinal cord injury; head injury; neurogenic inflammations; pain; brain reperfusion injuries; psoriatic arthritis; rheumatic arthritis; ankylosing spondylitis; osteoarthritis; inflammation; or cytokine-mediated chronic tissue degeneration, characterized by the step of administering a therapeutically effective amount, or a prophylactically effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof. 23. Method of treatment or prevention of allergic rhinitis, allergic conjunctivitis, eosinophilic granuloma, osteoporosis, arterial restenosis, arteriosclerosis, myocardial reperfusion injury, chronic glomerulonephritis, vernal conjunctivitis, cachexia, rejection of transplants or implants, indicated by the fact that it contains the step of administering a therapeutically effective amount, or a prophylactically effective amount of the compound according to claim 1 or its pharmaceutically acceptable salt. 24. Method of treatment or prevention of depression, memory impairment, monopolar depression, Parkinson's disease, Alzheimer's disease, acute and chronic multiple sclerosis, psoriasis, benign or malignant proliferative skin disease, atopic dermatitis, urticaria, cancer, tumor growth or carcinogenic invasion of normal tissue, characterized by the step of administering a therapeutically effective amount, or a prophylactically effective amount of the compound according to claim 1, or a pharmaceutically acceptable salt thereof. 25. Use of the compound from any of claims 1 to 18, or their pharmaceutically acceptable salts, indicated by the fact that they are used to produce a medicine for the treatment or prevention of the diseases listed in the previous claims 22, 23 or 24. 26. A compound from any of claims 1 to 18, or a pharmaceutically acceptable salt thereof, characterized in that it is used as a phosphodiesterase-4 inhibitor. 27. The use of a compound from any of claims 1 to 18, or their pharmaceutically acceptable salts, indicated by the fact that it is used to treat or prevent the diseases listed in previous claims 22, 23 or 24. 28. A pharmaceutical preparation of phosphodiesterase-4 inhibitor, characterized in that it contains an acceptable amount of a compound that inhibits phosphodiesterase-4, from any of claims 1 to 18, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier. 29. Compound according to claim 13, characterized in that it consists of N-cyclopropyl-1-[3-(1-oxido-3-pyridinylethynyl)phenyl]-1,4-dihydro[1,8]naphthyridin-4-one -3-carboxamide, or its pharmaceutically acceptable salts. 30. Pharmaceutical preparation, characterized in that it consists of a therapeutically effective amount of carboxamide or salt from claim 29, together with a pharmaceutically acceptable carrier. 31. The carboxamide or salt of claim 29, characterized in that it is used as a phosphodiesterase-4 inhibitor. 32. Use of carboxamides or salts from claim 29, characterized by the fact that they are used to produce a medicine for the treatment or prevention of diseases listed in the previous claims 22, 23 or 24. 33. The compound according to claim 1, characterized in that it consists of N-cyclopropyl-1-{3-[(1-oxidopyridin-3-yl)ethynyl]phenyl}-4-oxo-1,4-dihydro-1, 8-naphthyridine-3-carboxamide, or its pharmaceutically acceptable salts.